Mia Tuang Koh

Safety and immunogenicity of a tetravalent dengue vaccine in healthy children aged 2-11 years in Malaysia: A randomized, placebo-controlled, Phase III study ,

BACKGROUND Dengue disease is a major public health problem across the Asia-Pacific region for which there is no licensed vaccine or treatment. We evaluated the safety and immunogenicity of Phase III lots of a candidate vaccine (CYD-TDV) in children in Malaysia. METHODS In this observer-blind, placebo-controlled, Phase III study, children aged 2-11 years were randomized (4:1) to receive CYD-TDV or placebo at 0, 6 and 12 months. Primary endpoints included assessment of reactogenicity following each dose, adverse events (AEs) and serious AEs (SAEs) reported throughout the study, and immunogenicity expressed as geometric mean titres (GMTs) and distribution of dengue virus (DENV) neutralizing antibody titres. RESULTS 250 participants enrolled in the study (CYD-TDV: n=199; placebo: n=51). There was a trend for reactogenicity to be higher with CYD-TDV than with placebo post-dose 1 (75.4% versus 68.6%) and post-dose 2 (71.6% versus 62.0%) and slightly lower post-dose 3 (57.9% versus 64.0%). Unsolicited AEs declined in frequency with each subsequent dose and were similar overall between groups (CYD-TDV: 53.8%; placebo: 49.0%). Most AEs were of Grade 1 intensity and were transient. SAEs were reported by 5.5% and 11.8% of participants in the CYD-TDV and placebo groups, respectively. No deaths were reported. Baseline seropositivity against each of the four DENV serotypes was similar between groups, ranging from 24.0% (DENV-4) to 36.7% (DENV-3). In the CYD-TDV group, GMTs increased post-dose 2 for all serotypes compared with baseline, ranging from 4.8 (DENV-1) to 8.1-fold (DENV-3). GMTs further increased post-dose 3 for DENV-1 and DENV-2. Compared with baseline, individual titre increases ranged from 6.1-fold (DENV-1) to 7.96-fold (DENV-3). CONCLUSIONS This study demonstrated a satisfactory safety profile and a balanced humoral immune response against all four DENV serotypes for CYD-TDV administered via a three-dose regimen to children in Malaysia.

The predictive value of uvulo-palatoglossal junctional ulcers as an early clinical sign of exanthem subitum due to human herpesvirus 6.

BACKGROUND The clinical sign of uvulo-palatoglossal junctional (UPJ) ulcers was first noted in 1983 in a 5.5-month-old baby with exanthem subitum (ES). An earlier prospective clinical study showed that there was a strong association of UPJ ulcers and occurrence of ES with a positive predictive value of 95.3% and negative predictive value of 100%. OBJECTIVE To determine the value of uvulo-palatoglossal junctional (UPJ) ulcers as an early clinical sign of exanthem subitum (ES) due to human herpesvirus 6 (HHV 6) infection. STUDY DESIGN A case-control study of 20 febrile children with UPJ ulcers versus 26 febrile children without UPJ ulcers. These children were followed up for any development of ES and investigated for human herpesvirus 6 (HHV 6) as the causative agents of the febrile episodes. RESULTS In this study, 20 out of 46 febrile children aged 3 months to 3 years with UPJ ulcers were virologically and/or serologically confirmed to be due to primary HHV 6 infection. The rest of the 26 children without ulcers did not have HHV 6 infection. Of the 20 children with UPJ ulcers, only 17 of the 19 children with adequate follow-up till subsidence of fever developed ES. None of the 26 children without UPJ ulcers developed ES. CONCLUSION Statistically, there was a significant association of UPJ ulcers as an early sign of ES with a positive predictive value of 89.5% and negative predictive value of 100%. This finding also suggests that the presence of UPJ ulcers is a useful pathognomic clinical sign of symptomatic primary HHV 6 infection.

Immunodominant IgM and IgG Epitopes Recognized by Antibodies Induced in Enterovirus A71-Associated Hand, Foot and Mouth Disease Patients

Enterovirus A71 (EV-A71) is one of the main causative agents of hand, foot and mouth disease (HFMD). Unlike other enteroviruses that cause HFMD, EV-A71 is more frequently associated with severe neurological complications and fatality. To date, no effective licensed antivirals are available to combat EV-A71 infection. Little is known about the immunogenicity of viral non-structural proteins in humans. Previous studies have mainly focused on characterization of epitopes of EV-A71 structural proteins by using immunized animal antisera. In this study, we have characterized human antibody responses against the structural and non-structural proteins of EV-A71. Each viral protein was cloned and expressed in either bacterial or mammalian systems, and tested with antisera by western blot. Results revealed that all structural proteins (VP1-4), and non-structural proteins 2A, 3C and 3D were targets of EV-A71 IgM, whereas EV-A71 IgG recognized all the structural and non-structural proteins. Sixty three synthetic peptides predicted to be immunogenic in silico were synthesized and used for the characterization of EV-A71 linear B-cell epitopes. In total, we identified 22 IgM and four IgG dominant epitopes. Synthetic peptide PEP27, corresponding to residues 142–156 of VP1, was identified as the EV-A71 IgM-specific immunodominant epitope. PEP23, mapped to VP1 41–55, was recognized as the EV-A71 IgG cross-reactive immunodominant epitope. The structural protein VP1 is the major immunodominant site targeted by anti-EV-A71 IgM and IgG antibodies, but epitopes against non-structural proteins were also detected. These data provide new understanding of the immune response to EV-A71 infection, which benefits the development of diagnostic tools, potential therapeutics and subunit vaccine candidates.

Under-recognized pertussis in adults from Asian countries: a cross-sectional seroprevalence study in Malaysia, Taiwan and Thailand.

SUMMARY Surveillance data on the burden of pertussis in Asian adults are limited. This cross-sectional study evaluated the prevalence of serologically confirmed pertussis in adults with prolonged cough in Malaysia, Taiwan and Thailand. Adults (⩾19 years) with cough lasting for ⩾14 days without other known underlying cause were enrolled from outpatient clinics of seven public and/or private hospitals. Single blood samples for anti-pertussis toxin antibodies (anti-PT IgG) were analysed and economic impact and health-related quality of life (EQ-5D) questionnaires assessed. Sixteen (5·13%) of the 312 chronically coughing adults had serological evidence of pertussis infection within the previous 12 months (anti-PT IgG titre ⩾62·5 IU/ml). Three of them were teachers. Longer duration of cough, paroxysms (75% seroconfirmed, 48% non-seroconfirmed) and breathlessness/chest pain (63% seroconfirmed, 36% non-seroconfirmed) were associated with pertussis (P < 0·04). Of the seroconfirmed patients, the median total direct medical cost per pertussis episode in public hospitals (including physician consultations and/or emergency room visits) was US

Endotoxin tests in patients with sepsis

13 in Malaysia, US

Hospitalised Malaysian children with pandemic (H1N1) 2009 influenza: clinical characteristics, risk factors for severe disease and comparison with the 2002–2007 seasonal influenza

83 in Taiwan (n = 1) and US

Neonatal liver abscess following abdominal surgery for necrotizing enterocolitis

26 in Thailand. The overall median EQ-5D index score of cases was 0·72 (range 0·42–1·00). Pertussis should be considered in the aetiology of adults with a prolonged or paroxysmal cough, and vaccination programmes considered.

Cytokine and Chemokine Profiling in Patients with Hand, Foot and Mouth Disease in Singapore and Malaysia

A new whole blood agglutination assay and a plasma Limulus amoebocyte lysate (LAL) assay for the measurement of endotoxin were evaluated for the diagnosis of sepsis and septic shock in 73 intensive care patients and 50 normal blood donors. All samples were blinded to the operators performing the tests. The endotoxin test results were compared with blood culture and clinical observations of sepsis progression. Endotoxin was detectable in 34 of 38 patients with culture positive Gram-negative bacteraemia, 2 of 11 patients with Gram-positive bacteraemia, 3 of the 7 patients with suspected sepsis, whose blood culture was repeatedly negative, and 1 of 17 non-septic patients. All blood donors were found to be negative for endotoxin. In 3 patients monitored during the course of their illness, the endotoxin assays correlated closely. We conclude that endotoxin measurement was valuable in the care of patients with sepsis and that the whole blood agglutination assay was rapid and simple to perform.

Diphtheric encephalitis and brain neuroimaging features

INTRODUCTION The pandemic caused by the H1N1 influenza virus in 2009 resulted in extensive morbidity and mortality worldwide. As the virus was a novel virus, there was limited data available on the clinical effects of the virus on children in Malaysia. Herein, we describe the clinical characteristics of children hospitalised with H1N1 influenza in a tertiary care centre; we also attempted to identify the risk factors associated with disease severity. METHODS In this retrospective study, we compared the characteristics of the children who were admitted into the University of Malaya Medical Centre, Malaysia, for H1N1 influenza during the pandemic with those who were admitted for seasonal influenza in 2002-2007. RESULTS Among the 77 children (aged ≤ 12 years) admitted to the centre due to H1N1 influenza from 1 July 2009-30 June 2010, nearly 60% were aged < 6 years and 40.3% had an underlying medical condition. The top three underlying medical conditions were bronchial asthma (14.3%), cardiac disease (10.4%) and neurological disorder (11.7%). The risk factors for severe disease were age < 2 years, underlying bronchial asthma and chronic lung disease. The three patients who died had a comorbid medical condition. The underlying cause of the deaths was acute respiratory distress syndrome or shock. CONCLUSION The clinical presentation of the children infected with the pandemic (H1N1) 2009 influenza virus did not differ significantly from that of children infected with seasonal influenza. However, there were more complaints of fever, cough and vomiting in the former group.

The incidence of human herpesvirus 6 infection in children with febrile convulsion admitted to the University Hospital, Kuala Lumpur.

Neonatal liver abscess may stem from seeding of micro-organisms as part of a bacteremic process or from the portal vein, umbilical vein, or perivenous lymphatics. Liver abscess associated with neonatal necrotizing enterocolitis (NEC) has rarely been documented. We describe a case of a term neonate who developed NEC with intestinal perforation, requiring gut resection. This was followed by the formation of a liver abscess that eventually needed open drainage. It is believed that the causative organism (Escherichia coli) had disseminated to the liver via the portal vein from the necrotic bowel or during surgery.