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Background: Parents often express concerns about feeding difficulties in their child. We hypothesized that these parental concerns were associated with adverse growth status in early childhood. We aimed to determine the prevalence of such concerns and whether these concerns were associated with adverse growth status in early childhood., Methods: We performed a cross-sectional study among healthy children aged 12-36 months attending three well-baby clinics in three urban areas in Malaysia and Singapore between December 2016 and February 2017. Parents were interviewed for concerns about their child's feeding and presence of behavioral and organic red flags for feeding difficulties. We defined growth faltering as weight-for-age < 3rd centile and short stature as height-for-age < 3rd centile according to World Health Organization Growth Standards., Results: Of the 303 children studied (boys = 160, 52.8%; mean [± SD] chronological age at interview 21.3 [± 4.0] months), 13% (n = 38/292) had growth faltering and 19.5% (n = 50/256) had short stature. Overall, 36.3% (n = 110) of parents expressed concerns about their child's feeding behavior. Sixty-eight percent (n = 206) of parents reported presence of at least one behavioral and 18.5% (n = 56) had at least one organic red flag for feeding difficulties, respectively. 9.9% (n = 30) had both behavioral and organic red flags for feeding difficulties. Growth faltering was significantly associated with parental concern about feeding (odds ratio [OR] 3.049, p < 0.001), food refusal (OR 4.047, p < 0.001) and presence of at least one organic red flag (OR 2.625, p = 0.012)., Conclusion: We found that parental concerns about their child's feeding to be common. Presence of parental concern, food refusal in the child and presence of organic red flags for feeding difficulties are associated growth faltering in early childhood., (Copyright © 2019. Published by Elsevier B.V.)

Dengue is a major public health problem worldwide. Although several drug candidates have been evaluated in randomized controlled trials, none has been effective and at present, early recognition of severe dengue and timely supportive care are used to reduce mortality. While the first dengue vaccine was recently licensed, and several other candidates are in late stage clinical trials, future decisions regarding widespread deployment of vaccines and/or therapeutics will require evidence of product safety, efficacy and effectiveness. Standard, quantifiable clinical endpoints are needed to ensure reproducibility and comparability of research findings. To address this need, we established a working group of dengue researchers and public health specialists to develop standardized endpoints and work towards consensus opinion on those endpoints. After discussion at two working group meetings and presentations at international conferences, a Delphi methodology-based query was used to finalize and operationalize the clinical endpoints. Participants were asked to select the best endpoints from proposed definitions or offer revised/new definitions, and to indicate whether contributing items should be designated as optional or required. After the third round of inquiry, 70% or greater agreement was reached on moderate and severe plasma leakage, moderate and severe bleeding, acute hepatitis and acute liver failure, and moderate and severe neurologic disease. There was less agreement regarding moderate and severe thrombocytopenia and moderate and severe myocarditis. Notably, 68% of participants agreed that a 50,000 to 20,000 mm3 platelet range be used to define moderate thrombocytopenia; however, they remained divided on whether a rapid decreasing trend or one platelet count should be case defining. While at least 70% agreement was reached on most endpoints, the process identified areas for further evaluation and standardization within the context of ongoing clinical studies. These endpoints can be used to harmonize data collection and improve comparability between dengue clinical trials., Competing Interests: Beth-Ann G. Coller is an employee, shareholder and patent inventor of Merck & Co., Inc., Kenilworth, New Jersey, United States of America. Robert Edelman is a paid consultant to Takeda Pharmaceutical Company vaccine trials for service as Chairman of the Data and Safety Monitoring Board (DSMB) of Takeda's Tetravalent Dengue Vaccine Program. Alexander C. Schmidt is an employee and shareholder of the GlaxoSmithKline plc (GSK), Brentford, London, United Kingdom. Stephen J. Thomas has performed both paid and unpaid consultations and safety reviews for GSK Vaccines, Merck, Takeda, Sanofi Pasteur, Chugai Pharma, Themisbio, and Primevax. Derek Wallace is an employee of Takeda Pharmaceuticals International AG, Zurich, Switzerland. Bridget Wills is a paid consultant on the DSMB for the Takeda vaccine trials. No other authors have declared that a competing interest exists.

Background: Dengue is the commonest vector-borne infection worldwide. It is often associated with thrombocytopenia, and prophylactic platelet transfusion is widely used despite the dearth of robust evidence. We aimed to assess the efficacy and safety of prophylactic platelet transfusion in the prevention of bleeding in adults with dengue and thrombocytopenia., Methods: We did an open-label, randomised, superiority trial in five hospitals in Singapore and Malaysia. We recruited patients aged at least 21 years who had laboratory-confirmed dengue (confirmed or probable) and thrombocytopenia (≤20 000 platelets per μL), without persistent mild bleeding or any severe bleeding. Patients were assigned (1:1), with randomly permuted block sizes of four or six and stratified by centre, to receive prophylactic platelet transfusion in addition to supportive care (transfusion group) or supportive care alone (control group). In the transfusion group, 4 units of pooled platelets were given each day when platelet count was 20 000 per μL or lower; supportive care consisted of bed rest, fluid therapy, and fever and pain medications. The primary endpoint was clinical bleeding (excluding petechiae) by study day 7 or hospital discharge (whichever was earlier), analysed by intention to treat. Safety outcomes were analysed according to the actual treatment received. This study was registered with ClinicalTrials.gov, number NCT01030211, and is completed., Findings: Between April 29, 2010, and Dec 9, 2014, we randomly assigned 372 patients to the transfusion group (n=188) or the control group (n=184). The intention-to-treat analysis included 187 patients in the transfusion group (one patient was withdrawn immediately) and 182 in the control group (one was withdrawn immediately and one did not have confirmed or probable dengue). Clinical bleeding by day 7 or hospital discharge occurred in 40 (21%) patients in the transfusion group and 48 (26%) patients in the control group (risk difference -4·98% [95% CI -15·08 to 5·34]; relative risk 0·81 [95% CI 0·56 to 1·17]; p=0·16). 13 adverse events occurred in the transfusion group and two occurred in the control group (5·81% [-4·42 to 16·01]; 6·26 [1·43 to 27·34]; p=0·0064). Adverse events that were possibly, probably, or definitely related to transfusion included three cases of urticaria, one maculopapular rash, one pruritus, and one chest pain, as well as one case each of anaphylaxis, transfusion-related acute lung injury, and fluid overload that resulted in serious adverse events. No death was reported., Interpretation: In adult patients with dengue and thrombocytopenia, prophylactic platelet transfusion was not superior to supportive care in preventing bleeding, and might be associated with adverse events., Funding: National Medical Research Council, Singapore., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Introduction: Home ventilation (HV) for children is growing rapidly worldwide. The aim was to describe (1) the sociodemographic characteristics of children on HV and (2) the indications for, means and outcome of initiating HV in children from a developing country., Methodology: This retrospective study included patients sent home on noninvasive or invasive ventilation, over 13 years, by the pediatric respiratory unit in a single center. Children who declined treatment were excluded., Results: Seventy children were initiated on HV: 85.7% on noninvasive ventilation, 14.3% on invasive ventilation. There was about a threefold increase from 2001-2008 (n = 18) to 2009-2014 (n = 52). Median (range) age of initiating HV was 11 (1-169) months and 73% of children were <2 years old. Common indications for HV were respiratory (57.2%), chest/spine anomalies (11.4%), and neuromuscular (10.0%). Fifty-two percent came off their devices with a median (interquartile range) usage duration of 12 (4.8, 21.6) months. Ten children (14.3%) died with one avoidable death. Children with neuromuscular disease were less likely to come off their ventilator (0.0%) compared to children with respiratory disease (62.1%). Forty-one percent of parents bought their equipment, whereas 58.6% borrowed their equipment from the medical social work department and other sources., Conclusion: HV in a resource-limited country is possible. Children with respiratory disease made up a significant proportion of those requiring HV and were more likely to be weaned off. The mortality rate was low. The social work department played an important role in facilitating early discharge. Pediatr Pulmonol. 2017;52:500-507. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Objectives: Pediatric severe sepsis remains a significant global health problem without new therapies despite many multicenter clinical trials. We compared children managed with severe sepsis in European and U.S. PICUs to identify geographic variation, which may improve the design of future international studies., Design: We conducted a secondary analysis of the Sepsis PRevalence, OUtcomes, and Therapies study. Data about PICU characteristics, patient demographics, therapies, and outcomes were compared. Multivariable regression models were used to determine adjusted differences in morbidity and mortality., Setting: European and U.S. PICUs., Patients: Children with severe sepsis managed in European and U.S. PICUs enrolled in the Sepsis PRevalence, OUtcomes, and Therapies study., Interventions: None., Measurements and Main Results: European PICUs had fewer beds (median, 11 vs 24; p < 0.001). European patients were younger (median, 1 vs 6 yr; p < 0.001), had higher severity of illness (median Pediatric Index of Mortality-3, 5.0 vs 3.8; p = 0.02), and were more often admitted from the ward (37% vs 24%). Invasive mechanical ventilation, central venous access, and vasoactive infusions were used more frequently in European patients (85% vs 68%, p = 0.002; 91% vs 82%, p = 0.05; and 71% vs 50%; p < 0.001, respectively). Raw morbidity and mortality outcomes were worse for European compared with U.S. patients, but after adjusting for patient characteristics, there were no significant differences in mortality, multiple organ dysfunction, disability at discharge, length of stay, or ventilator/vasoactive-free days., Conclusions: Children with severe sepsis admitted to European PICUs have higher severity of illness, are more likely to be admitted from hospital wards, and receive more intensive care therapies than in the United States. The lack of significant differences in morbidity and mortality after adjusting for patient characteristics suggests that the approach to care between regions, perhaps related to PICU bed availability, needs to be considered in the design of future international clinical trials in pediatric severe sepsis.

Introduction: The increasing incidence of dengue among adults in Malaysia and other countries has important implications for health services. Before 2004, in order to cope with the surge in adult dengue admissions, each of the six medical wards in a university hospital took turns daily to admit and manage patients with dengue. Despite regular in-house training, the implementation of the WHO 1997 dengue case management guidelines by the multiple medical teams was piecemeal and resulted in high variability of care. A restructuring of adult dengue inpatient service in 2004 resulted in all patients being admitted to one ward under the care of the infectious disease unit. Hospital and Intensive Care Unit admission criteria, discharge criteria and clinical laboratory testing were maintained unchanged throughout the study period., Objectives: To evaluate the impact of cohorting adult dengue patients on the quality of care and the clinical outcome in a university hospital in Malaysia., Methods: A pre (2003) and post-intervention (2005-6) retrospective study was undertaken., Intervention: Cohorting all dengue patients under the care of the Infectious Disease team in a designated ward in 2004., Results: The number of patients enrolled was 352 in 2003, 785 in 2005 and 1158 in 2006. The evaluation and detection of haemorrhage remained high (>90%) and unchanged throughout the study period. The evaluation of plasma leakage increased from 35.4% pre-intervention to 78.8% post-intervention (p = <0.001) while its detection increased from 11.4% to 41.6% (p = <0.001). Examination for peripheral perfusion was undertaken in only 13.1% of patients pre-intervention, with a significant increase post-intervention, 18.6% and 34.2% respectively, p = <0.001. Pre-intervention, more patients had hypotension (21.5%) than detected peripheral hypoperfusion (11.4%), indicating that clinicians recognised shock only when patients developed hypotension. In contrast, post-intervention, clinicians recognised peripheral hypoperfusion as an early sign of shock. The highest haematocrit was significantly higher post-intervention but the lowest total white cell counts and platelet counts remained unchanged. A significant and progressive reduction in the use of platelet transfusions occurred, from 21.7% pre-intervention to 14.6% in 2005 and 5.2% in 2006 post-intervention, p<0.001. Likewise, the use of plasma transfusion decreased significantly from 6.1% pre-intervention to 4.0% and 1.6% in the post-intervention years of 2005 and 2006 respectively, p<0.001. The duration of intravenous fluid therapy decreased from 3 days pre-intervention to 2.5 days (p<0.001) post-intervention; the length of hospital stay reduced from 4 days pre- to 3 days (p<0.001) post-intervention and the rate of intensive care admission from 5.8% pre to 2.6% and 2.5% post-intervention, p = 0.005., Conclusion: Cohorting adult dengue patients under a dedicated and trained team of doctors and nurses led to a substantial improvement in quality of care and clinical outcome.

Aim: Lower respiratory tract infections (LRTIs) are an important cause of morbidity and mortality, especially in low income countries. The aim of this study was to determine risk factors of life-threatening LRTIs in hospitalised children in Malaysia., Methods: This retrospective study included children aged less than 18 years admitted for LRTIs over 13 months in a tertiary referral centre in Kuala Lumpur, Malaysia. Neonates, children with asthma and those with either no or a normal chest radiograph were excluded. Life-threatening infection was defined as that needing non-invasive ventilation or admission to the paediatric intensive care unit. Routine blood investigations and nasopharyngeal secretion results (bacterial and viral) were obtained. Chest radiographs were reviewed by a designated radiologist. Environmental data (rainfall, particulate matter ≤ 10 µm [PM10] and air pollution index [API]) was obtained from the respective government departments., Results: Three hundred and ninety-one episodes of LRTIs were included. Viruses were implicated in 48.5% of LRTIs, with respiratory syncytial virus (RSV) being detected in 44% of viral LRTIs. Forty-six (11.8%) children had life-threatening disease and the overall mortality rate was 1.3% (5 children). RSV was detected in 26% of children with life-threatening LRTIs. In multivariate logistic regression, chronic lung disease, presenting history of apnoea and signs of hypoxia, was associated with life threatening LRTIs. Increased LRTI admissions were associated with low rainfall but not PM10 nor API. Of those on follow-up, 39% had persistent respiratory symptoms., Conclusion: One in nine children admitted with LRTI had a life-threatening LRTI. The aetiology was viral in almost half of admitted children. RSV was detected in a quarter of children with life-threatening LRTIs. Children who present with LRTIs and either have chronic lung disease, presenting history of apnoea or signs of hypoxia, should be observed carefully as the risk of deterioration to life-threatening illness is high.

We report the results of an International Nosocomial Infection Control Consortium (INICC) surveillance study from January 2007-December 2012 in 503 intensive care units (ICUs) in Latin America, Asia, Africa, and Europe. During the 6-year study using the Centers for Disease Control and Prevention's (CDC) U.S. National Healthcare Safety Network (NHSN) definitions for device-associated health care-associated infection (DA-HAI), we collected prospective data from 605,310 patients hospitalized in the INICC's ICUs for an aggregate of 3,338,396 days. Although device utilization in the INICC's ICUs was similar to that reported from ICUs in the U.S. in the CDC's NHSN, rates of device-associated nosocomial infection were higher in the ICUs of the INICC hospitals: the pooled rate of central line-associated bloodstream infection in the INICC's ICUs, 4.9 per 1,000 central line days, is nearly 5-fold higher than the 0.9 per 1,000 central line days reported from comparable U.S. ICUs. The overall rate of ventilator-associated pneumonia was also higher (16.8 vs 1.1 per 1,000 ventilator days) as was the rate of catheter-associated urinary tract infection (5.5 vs 1.3 per 1,000 catheter days). Frequencies of resistance of Pseudomonas isolates to amikacin (42.8% vs 10%) and imipenem (42.4% vs 26.1%) and Klebsiella pneumoniae isolates to ceftazidime (71.2% vs 28.8%) and imipenem (19.6% vs 12.8%) were also higher in the INICC's ICUs compared with the ICUs of the CDC's NHSN., (Copyright © 2014 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Mosby, Inc. All rights reserved.)

Dengue infection is a major cause of morbidity and mortality in Malaysia. To date, much research on dengue infection conducted in Malaysia have been published. One hundred and sixty six articles related to dengue in Malaysia were found from a search through a database dedicated to indexing all original data relevant to medicine published between the years 2000-2013. Ninety articles with clinical relevance and future research implications were selected and reviewed. These papers showed evidence of an exponential increase in the disease epidemic and a varying pattern of prevalent dengue serotypes at different times. The early febrile phase of dengue infection consist of an undifferentiated fever. Clinical suspicion and ability to identify patients at risk of severe dengue infection is important. Treatment of dengue infection involves judicious use of volume expander and supportive care. Potential future research areas are discussed to narrow our current knowledge gaps on dengue infection.

Plasma leakage in severe dengue has been postulated to be associated with skewed cytokine immune responses. In this study, the association of cytokines with vascular permeability in dengue patients was investigated. Human serum samples collected from 48 persons (13 with dengue fever, 29 with dengue hemorrhagic fever, and 6 healthy) were subjected to cytokines analysis by using Luminex Multiplex Technology. Selected serum samples from patients with dengue hemorrhagic fever sera and recombinant human cytokines were then tested for roles on inducing vascular permeability by treatment of human umbilical vein endothelial cells. Confocal immunofluorescence staining indicated morphologic alteration of human umbilical vein endothelial cells treated with serum samples from patients with dengue hemorrhagic fever compared with serum samples from healthy persons. The findings suggest that cytokines produced during dengue hemorrhagic infections could induce alterations in the vascular endothelium, which may play a fundamental role in the pathophysiology of dengue.

Hemophagocytic syndrome is a potentially fatal disorder. It is being increasingly reported but remained under-recognized in dengue. Most reported cases were in association with plasma leakage and shock but multi-organ impairment was also observed. We describe the time-lines of 6 cases of confirmed dengue with varying severities of hemophagocytosis. All had persistent fever, cytopenia and elevated transaminases with markedly elevated ferritin levels during and beyond the plasma leakage phase. Acute renal failure and central nervous system manifestation were observed in two patients. Morphological hemophagocytosis was demonstrated in three patients. All survivors showed clinical and biochemical resolution of hemophagocytosis indicating its transient nature. Persistence of fever and cytopenia together with multi-organ dysfunction, out of proportion to and beyond the plasma leakage phase should prompt clinicians to consider this phenomenon., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: Dengue is an important medical problem, with symptoms ranging from mild dengue fever to severe forms of the disease, where vascular leakage leads to hypovolemic shock. Cytokines have been implicated to play a role in the progression of severe dengue disease; however, their profile in dengue patients and the synergy that leads to continued plasma leakage is not clearly understood. Herein, we investigated the cytokine kinetics and profiles of dengue patients at different phases of illness to further understand the role of cytokines in dengue disease., Methods and Findings: Circulating levels of 29 different types of cytokines were assessed by bead-based ELISA method in dengue patients at the 3 different phases of illness. The association between significant changes in the levels of cytokines and clinical parameters were analyzed. At the febrile phase, IP-10 was significant in dengue patients with and without warning signs. However, MIP-1β was found to be significant in only patients with warning signs at this phase. IP-10 was also significant in both with and without warning signs patients during defervescence. At this phase, MIP-1β and G-CSF were significant in patients without warning signs, whereas MCP-1 was noted to be elevated significantly in patients with warning signs. Significant correlations between the levels of VEGF, RANTES, IL-7, IL-12, PDGF and IL-5 with platelets; VEGF with lymphocytes and neutrophils; G-CSF and IP-10 with atypical lymphocytes and various other cytokines with the liver enzymes were observed in this study., Conclusions: The cytokine profile patterns discovered between the different phases of illness indicate an essential role in dengue pathogenesis and with further studies may serve as predictive markers for progression to dengue with warning signs.

Objective: To evaluate the existing WHO dengue classification across all age groups and a wide geographical range and to develop a revised evidence-based classification that would better reflect clinical severity., Methods: We followed suspected dengue cases daily in seven countries across South-east Asia and Latin America and then categorised them into one of three intervention groups describing disease severity according to the overall level of medical and nursing support required. Using a pre-defined analysis plan, we explored the clinical and laboratory profiles characteristic of these intervention categories and presented the most promising options for a revised classification scheme to an independent group of WHO dengue experts for consideration. Potential warning signs were also evaluated by comparing contemporaneous data of patients who progressed to severe disease with the data of those who did not., Results: A total of 2259 patients were recruited during 2006-2007 and 230 (13%) of the 1734 laboratory-confirmed patients required major intervention. Applying the existing WHO system, 47/210 (22%) of patients with shock did not fulfil all the criteria for dengue haemorrhagic fever. However, no three-tier revision adequately described the different severity groups either. Inclusion of readily discernible complications (shock/severe vascular leakage and/or severe bleeding and/or severe organ dysfunction) was necessary to devise a system that identified patients requiring major intervention with sufficient sensitivity and specificity to be practically useful. Only a small number of subjects (5%) progressed to severe disease while under observation; several warning signs were identified, but much larger studies are necessary to fully characterize features associated with disease progression., Conclusions: Based on these results, a revised classification system comprised of two entities, 'Dengue' and 'Severe Dengue', was proposed and has now been incorporated into the new WHO guidelines., (© 2011 Blackwell Publishing Ltd.)

Background: In view of the long term discussion on the appropriateness of the dengue classification into dengue fever (DF), dengue haemorrhagic fever (DHF) and dengue shock syndrome (DSS), the World Health Organization (WHO) has outlined in its new global dengue guidelines a revised classification into levels of severity: dengue fever with an intermediary group of "dengue fever with warning sings", and severe dengue. The objective of this paper was to compare the two classification systems regarding applicability in clinical practice and surveillance, as well as user-friendliness and acceptance by health staff., Methods: A mix of quantitative (prospective and retrospective review of medical charts by expert reviewers, formal staff interviews), semi-quantitative (open questions in staff interviews) and qualitative methods (focus group discussions) were used in 18 countries. Quality control of data collected was undertaken by external monitors., Results: The applicability of the DF/DHF/DSS classification was limited, even when strict DHF criteria were not applied (13.7% of dengue cases could not be classified using the DF/DHF/DSS classification by experienced reviewers, compared to only 1.6% with the revised classification). The fact that some severe dengue cases could not be classified in the DF/DHF/DSS system was of particular concern. Both acceptance and perceived user-friendliness of the revised system were high, particularly in relation to triage and case management. The applicability of the revised classification to retrospective data sets (of importance for dengue surveillance) was also favourable. However, the need for training, dissemination and further research on the warning signs was highlighted., Conclusions: The revised dengue classification has a high potential for facilitating dengue case management and surveillance.

Objective: To determine the factors that predict outcome of noninvasive ventilation (NIV) in critically ill children., Design: Prospective observational study., Setting: Multidisciplinary pediatric intensive care unit of a university hospital in Malaysia., Patients: Patients admitted to the pediatric intensive care unit from July 2004 to December 2006 for respiratory support due to acute respiratory failure and those extubated from invasive mechanical ventilation., Interventions: NIV was used as an alternative means of respiratory support for all children. In patients who had prior invasive mechanical ventilation, NIV was used to facilitate extubation, or it was used after a failed extubation. The children were assigned to the nonresponders group (intubation was needed) or responders group (intubation was avoided totally or for at least 5 days). The physiologic variables were monitored before, at 6 hrs, and 24 hrs of NIV., Measurements and Main Results: Of 278 patients, 129 were admissions for management of acute respiratory failure and 149 patients received NIV to facilitate extubation (n = 98) or for a failed extubation (n = 48). Their median age and weight were 8.7 months (interquartile range, 3.1-33.1 months) and 5.5 kg (interquartile range, 3.3-10.8 kg), respectively. Intubation was avoided for > 5 days in 79.1% (n = 220). No significant difference in age or weight of responders and nonresponders was observed. The cardiorespiratory variables in all patients improved, but significant differences between the two groups were noted at 6 hrs and 24 hrs after NIV., Conclusions: NIV was a feasible strategy of respiratory support to avoid intubation in > 75% of children in this study. A higher Pediatric Risk of Mortality II score, sepsis at initiation of NIV, an abnormal respiratory rate, and a higher requirement of Fio2 may be predictive factors of NIV failure.

Children aged 11 to <24 months received 2 intranasal doses of live attenuated influenza vaccine (LAIV) or placebo, 35+/-7 days apart. Dose 1 was administered concomitantly with a combined measles, mumps, and rubella vaccine (Priorix). Seroresponses to measles and mumps were similar between groups. Compared with placebo, response rates to rubella in LAIV+Priorix recipients were statistically lower at a 15 IU/mL threshold (83.9% vs 78.0%) and the prespecified noninferiority criteria were not met. In a post hoc analysis using an alternate widely accepted threshold of 10 IU/mL, the noninferiority criteria were met (93.4% vs 89.8%). Concomitant administration with Priorix did not affect the overall influenza protection rate of LAIV (78.4% and 63.8% against antigenically similar influenza strains and any strain, respectively)., (Copyright (c) 2009 Elsevier Ltd. All rights reserved.)

The World Health Organization (WHO) dengue classification scheme for dengue fever (DF) and dengue haemorrhagic fever (DHF)/dengue shock syndrome (DSS) has been adopted as the standard for diagnosis, clinical management and reporting. In recent years, difficulties in applying the WHO case classification have been reported in several countries. A multicenter study was carried out in Asia and Latin America to analyze the variation and utility of dengue clinical guidelines (DCGs) taking as reference the WHO/PAHO guidelines (1994) and the WHO/SEARO guidelines (1998). A document analysis of 13 dengue guidelines was followed by a questionnaire and Focus Group discussions (FGDs) with 858 health care providers in seven countries. Differences in DCGs of the 13 countries were identified including the concept of warning signs, case classification, use of treatment algorithms and grading into levels of severity. The questionnaires and FGDs revealed (1) inaccessibility of DCGs, (2) lack of training, (3) insufficient number of staff to correctly apply the DCGs at the frontline and (4) the unavailability of diagnostic tests. The differences of the DCGs and the inconsistency in their application suggest a need to re-evaluate and standardise DCGs. This applies especially to case classification and case management.

Dengue infections pose a huge burden to health care providers in most tropical countries. Careful clinical examination and history-taking supplemented by newer rapid diagnostic tests may lead to early etiological diagnosis. For severe dengue, early recognition of vascular permeability followed by rapid physiological replacement of fluids is life-saving. Prognosis of patients depends upon optimum management, an outcome that requires preparation via organization, training, and use of evidence-based practice guidelines.

Live attenuated influenza vaccine (LAIV) provides a useful tool to rapidly immunize populations in the developing world to prevent influenza outbreaks. In this noninferiority trial conducted in Asia and South America, where oral poliovirus vaccine (OPV) is still used, 2503 children aged 6 to <36 months with three polio immunizations were randomized to receive LAIV+OPV, placebo+OPV, or LAIV only. Immune responses in children receiving concomitant LAIV+OPV were noninferior to those observed in recipients of either vaccine alone. Response rates for different poliovirus types were similar in recipients of LAIV+OPV and placebo+OPV. Response rates to all influenza strains were similar in LAIV+OPV and LAIV-only recipients. Concomitant OPV and LAIV were safely administered to young children.

Despite the growing worldwide burden of dengue fever, the global economic impact of dengue illness is poorly documented. Using a common protocol, we present the first multicountry estimates of the direct and indirect costs of dengue cases in eight American and Asian countries. We conducted prospective studies of the cost of dengue in five countries in the Americas (Brazil, El Salvador, Guatemala, Panama, and Venezuela) and three countries in Asia (Cambodia, Malaysia, and Thailand). All studies followed the same core protocol with interviews and medical record reviews. The study populations were patients treated in ambulatory and hospital settings with a clinical diagnosis of dengue. Most studies were performed in 2005. Costs are in 2005 international dollars (I$). We studied 1,695 patients (48% pediatric and 52% adult); none died. The average illness lasted 11.9 days for ambulatory patients and 11.0 days for hospitalized patients. Among hospitalized patients, students lost 5.6 days of school, whereas those working lost 9.9 work days per average dengue episode. Overall mean costs were I$514 and I$1,394 for an ambulatory and hospitalized case, respectively. With an annual average of 574,000 cases reported, the aggregate annual economic cost of dengue for the eight study countries is at least I$587 million. Preliminary adjustment for under-reporting could raise this total to $1.8 billion, and incorporating costs of dengue surveillance and vector control would raise the amount further. Dengue imposes substantial costs on both the health sector and the overall economy.

The rapid diagnosis and subtyping of influenza is particularly important in areas where avian influenza (H5N1) is present. The ability to recognise both typical and atypical presentations of influenza is also critical in such settings. A six-month-old male child who visited a H5N1-affected area subsequently died from a severe febrile diarrhoeal illness with minimal respiratory symptoms, and was initially diagnosed with influenza A of an unknown subtype. The final microbiological results showed a highly unusual combination of influenza A (H3N2) and Campylobacter jejuni infection.

We describe cerebral salt wasting syndrome (CSWS) in a 5-year-old female child with Down syndrome who had acute myelopathy secondary to chronic atlantoaxial subluxation and fracture dislocation of the odontoid process. The patient developed hyponatraemia associated with excessive urine output and elevated urine sodium concentration following her injury. An administered volume-for-volume replacement of urine loss with 0.9% sodium chloride resulted in an excellent outcome. This patient illustrates the importance of ascertaining CSWS in children with spinal cord disorders, in addition to the syndrome of inappropriate antidiuretic hormone (SIADH) secretion and diabetes insipidus (DI) commonly encountered following a central nervous system (CNS) injury, as the specific treatment approaches is clearly associated with an excellent outcome.

Although the disease burden of dengue is increasing, the impact on the quality of life (QoL) has not been investigated. A study to determine the QoL of confirmed dengue patients using the EuroQol visual thermometer scale was carried out at the University Malaya Medical Center. Of the 207 participants, 40% were ambulatory and 60% were hospitalized. Of eight health domains, 6.2 and 5.0 domains were affected in the hospitalized and ambulatory cohorts, respectively (P < 0.001), with cognition and interpersonal activities affected most. All patients experienced a drastic decrease in their QoL from the onset of symptoms. The QoL deteriorated to the lowest point (40% of healthy status) between the third and seventh days of illness. The duration of impaired QoL (9 days for ambulatory or 13 days for hospitalized patients) was longer than the duration of fever (5 and 7 days, respectively). Symptomatic dengue has major effects on patients' health.

Background: Difficulties in the classification of dengue infection have been documented. Such difficulties could be due to the low awareness of the World Health Organization diagnostic guidelines among clinicians., Objective: To study the diagnostic practices of clinicians in classifying patients as dengue fever (DF) or dengue haemorrhagic fever (DHF)/dengue shock syndrome (DSS) at the time of discharge during an outbreak., Methods: A prospective descriptive study of clinical features and disease classification in adult and pediatric dengue patients in the University of Malaya Medical Centre., Results: Five hundred and twenty adult and 191 pediatric patients were enrolled. Thrombocytopenia and evidence of plasma leakage were present in 8% of adult and 19% of pediatric patients. Of these, 93% and 49%, respectively, were given the discharge diagnoses of DF instead of DHF/DSS. Hemoconcentration, serous effusion and thrombocytopenia were not recognized in clinicians' discharge diagnosis of DHF/DSS for adult patients. The receiver operating characteristic (ROC) curve suggested a lack of consistency in the use of WHO guidelines in establishing DHF/DSS in adult patients, while implying otherwise for pediatric patients., Conclusion: DHF/DSS is an under-recognized condition by clinicians managing these patients. This can affect the case fatality rate of DHF/DSS and the economic burden of the disease. The lack of awareness in disease manifestations especially plasma leakage, can lead to delayed recognition of DHF/DSS.

Background: This study was designed to evaluate the efficacy and safety of cold-adapted influenza vaccine, trivalent (CAIV-T) against culture-confirmed influenza in children 12 to <36 months of age during 2 consecutive influenza seasons at multiple sites in Asia., Methods: In year 1, 3174 children 12 to <36 months of age were randomized to receive 2 doses of CAIV-T (n = 1900) or placebo (n = 1274) intranasally > or =28 days apart. In year 2, 2947 subjects were rerandomized to receive 1 dose of CAIV-T or placebo., Results: Mean age at enrollment was 23.5 +/- 7.4 months. In year 1, efficacy of CAIV-T compared with placebo was 72.9% [95% confidence interval (CI): 62.8-80.5%] against antigenically similar influenza subtypes, and 70.1% (95% CI: 60.9-77.3%) against any strain. In year 2, revaccination with CAIV-T demonstrated significant efficacy against antigenically similar (84.3%; 95% CI: 70.1-92.4%) and any (64.2%; 95% CI: 44.2-77.3%) influenza strains. In year 1, fever, runny nose/nasal congestion, decreased activity and appetite, and use of fever medication were more frequent with CAIV-T after dose 1. Runny nose/nasal congestion after dose 2 (year 1) and dose 3 (year 2) and use of fever medication after dose 3 (year 2) were the only other events reported significantly more frequently in CAIV-T recipients., Conclusions: CAIV-T was well tolerated and effective in preventing culture-confirmed influenza illness over multiple and complex influenza seasons in young children in Asia.

Background: The current World Health Organisation (WHO) classification of dengue includes two distinct entities: dengue fever (DF) and dengue haemorrhagic fever (DHF)/dengue shock syndrome; it is largely based on pediatric cases in Southeast Asia. Dengue has extended to different tropical areas and older age groups. Variations from the original description of dengue manifestations are being reported., Objectives: To analyse the experience of clinicians in using the dengue case classification and identify challenges in applying the criteria in routine clinical practice., Method: Systematic literature review of post-1975 English-language publications on dengue classification., Results: Thirty-seven papers were reviewed. Several studies had strictly applied all four WHO criteria in DHF cases; however, most clinicians reported difficulties in meeting all four criteria and used a modified classification. The positive tourniquet test representing the minimum requirement of a haemorrhagic manifestation did not distinguish between DHF and DF. In cases of DHF thrombocytopenia was observed in 8.6-96%, plasma leakage in 6-95% and haemorrhagic manifestations in 22-93%. The low sensitivity of classifying DHF could be due to failure to repeat the tests or physical examinations at the appropriate time, early intravenous fluid therapy, and lack of adequate resources in an epidemic situation and perhaps a considerable overlap of clinical manifestations in the different dengue entities., Conclusion: A prospective multi-centre study across dengue endemic regions, age groups and the health care system is required which describes the clinical presentation of dengue including simple laboratory parameters in order to review and if necessary modify the current dengue classification.

An open lung biopsy was performed in 12 children with diffuse parenchymal lung disease. A definitive histopathological diagnosis was obtained from all procedures but determined treatment options in only 10 children (83%). Three (25%) children were ventilated for respiratory failure prior to the procedure. Four (44%) of the other 9 children required ventilatory support after the procedure. Three (25%) children developed post-op pneumothorax that resolved fully with chest tube drainage. There were no deaths as a direct result of the procedure. Open lung biopsy is useful in providing a definitive diagnosis in children with diffuse parenchymal lung disease and determining treatment in the majority of cases. The procedure was well-tolerated with minimal complications.

We compared 53 patients with Dengue shock syndrome (DSS) who received preventive transfusions with 53 who did not. Significant differences in the development of pulmonary edema and length of hospitalization (P<.05) and none in hemorrhage (P=.136) were observed. Preventive transfusions did not produce sustained improvements in the coagulation status in DSS.

A six-week-old male infant was admitted for investigation of cholestasis and pale stools. He became lethargic and apnoeic with prolonged seizures after a percutaneous liver biopsy. Subsequent investigations showed conjugated hyperbilirubinaemia, elevated liver enzymes, and hypoglycaemia. The radinuclide hepatobiliary scintigraphy was non-excretory. After an operative cholangiogram, the infant developed Addisonian-like crisis with bradycardia, hypotension, respiratory distress, metabolic acidosis, hypoglycaemia, hyponatraemia, and hyperkalaemia. Blood investigations confirmed congenital hypopituitarism. Hormone replacement therapy with L-thyroxine and cortisone acetate resulted in dissolution of jaundice and the reduction of the liver size.

Objective: Lack of direct access to tertiary pediatric intensive care services in rural hospitals may be associated with poorer outcome among critically ill children. Inter-hospital transport by non-specialized teams may also lead to increased morbidity and even mortality. We therefore studied the outcome of children with different accessibility to tertiary pediatric care in Malaysia., Methods: We prospectively compared the Pediatric Risk of Mortality (PRISM II) adjusted standardized mortality ratio (SMR), unanticipated deaths and length of stay of 131 patients transported from rural hospitals (limited access) with 215 transferred from the casualty wards or other in-hospital wards (direct access) to a tertiary pediatric ICU., Results: The transported patients were younger than the in-hospital patients (median age 1.0 versus 6.0 months, p=0.000) and were more likely to have respiratory diseases. Other baseline characteristics did not differ significantly. Differences in access to tertiary intensive care from community hospitals was associated with an extended median length of stay (4.0 versus 2.0 days, p=0.000) but did not affect SMR (0.92 versus 0.84, rate ratio 1.09, 95% CI 0.57-2.01; p=0.348) or percentage of unexpected deaths (4.8% versus 2.8%, p=0.485). The adjusted odds ratio for mortality (1.7, 95% CI 0.7-4.3) associated with transfer was not statistically significant (p=0.248)., Conclusions: The outcome of critically ill children transferred from community hospitals did not differ from that of those who develop ICU needs in the wards of a tertiary center, despite being transported by non-specialized teams. Outcome was not affected by initial inaccessibility to intensive care if the children finally received care in a tertiary center.

The purpose of this study was to identify the early indicators of hemorrhage in severe dengue infections in 114 patients; 24 patients had severe hemorrhage and 92 had no hemorrhage. The platelet counts were not predictive of bleeding. The duration of shock (OR, 2.11; 95% CI, 1.13 to 3.92; P =.019) and low-normal hematocrit at the time of shock (OR, 0.72; 95% CI, 0.55 to 0.95; P =.020) were risk factors of severe hemorrhage.

Background: Hand, foot, and mouth disease (HFMD) is endemic in Malaysia. In 1997, a large outbreak of enterovirus 71 (EV-71) associated HFMD resulted in 41 deaths due to severe left ventricular dysfunction and central nervous system infection with extensive damage to the medulla and pons. The clinical presentation in all these patients were rapid cardio-respiratory decompensation leading to cardiac arrest. Another large outbreak of HFMD with 55 fatal cases and a similar clinical picture was reported in Taiwan in 1998. In 2000, an outbreak of HFMD resulted in the deaths of three children who had rapid cardio-respiratory decompensation and one child who survived a central nervous system infection., Objectives: We set out to study the etiologic agent and mechanism involved in three children who presented to our hospital, two of whom died and one survived a central nervous system infection., Study Design: The clinical course of the disease was described. Throat, rectal swab and cerebrospinal fluid samples were subjected to viral isolation and viral isolates were identified by immunofluorescence, micro-neutralisation using human rhabdomyosarcoma (RD) cells, and reverse transcritpase polymerase chain reaction. Magnetic resonance imaging was performed on two of the patients., Results: Echovirus 7 was the sole pathogen isolated from three cases of acute encephalomyelitis, two of which were fatal due to severe left ventricular dysfunction resistant to inotropic support. The survivor had residual bulbar palsy, but is considered to have had a good neurological outcome., Conclusion: Echovirus 7 infection associated with encephalomyelitis could be fatal due to indirect involvement of the heart resulting in severe left ventricular dysfunction. In addition one of the children presented with hand, foot, and mouth disease, a syndrome that has not been previously associated with echovirus 7 infection.

Inhaled nitric oxide (iNO) improves oxygenation in term and near-term infants with persistent pulmonary hypertension of the newborn (PPHN) and decreases the need for treatment with extracorporeal membrane oxygenation (ECMO). This mode of treatment is currently being introduced in Malaysia. We report our preliminary experience using low dose inhaled nitric oxide (20 parts per million) in three newborn infants (meconium aspiration syndrome, primary PPHN and congenital diaphragmatic hernia) with severe PPHN who fulfilled criteria for ECMO with a mean oxygenation index (OI) of 40. Two of the infants showed rapid and sustained improvement in oxygenation with a reduction in oxygenation index (OI) over 24 hours. The infant with diaphragmatic hernia showed an initial improvement in OI, which was unsustained and subsequently died. All three infants did not show significant elevation of methemoglobin or nitrogen dioxide (NO2). Inhaled nitric oxide is an effective and safe treatment for severe PPHN that can be used in a developing country like Malaysia.

Mycoplasma pneumoniae is increasingly recognized as an important cause of community acquired pneumonia (CAP) in children. We determined the importance of M. pneumoniae as a causative agent in 170 children aged 1 month to 15 years who were hospitalized with CAP over a 6-month period. The diagnosis of M. pneumoniae infection was based on serological evidence obtained by a particle agglutination test (SERODIA-MYCO II). A positive serological diagnosis was made if the acute phase serum titer was more than 1:160 or paired samples taken 2-4 weeks apart showed a four-fold or greater rise in the serum titer. M. pneumoniae was identified as the causative agent in 40 (23.5%) children. Children with M. pneumoniae infection were more likely to be older than 3 years (OR 4.0 95%CI 1.8-9.1, p<0.001), Chinese (OR 4.3 95%CI 2.0-8.9, p<0.001), have a duration of illness longer than 7 days prior to admission (OR 6.0 95%CI 2.7-13.5, p<0.001) and have perihilar interstitial changes on chest X-ray (OR 4.6 95%CI 2.2-9.9, p<0.001). A significant number of hospital admissions for CAP in Malaysian children can be attributed to M. pneumoniae. It is important to identify these children so as to administer the most appropriate antibiotic treatment.

Twenty-two (42 per cent) out of 52 patients admitted with severe bronchiolitis to our Paediatric Intensive Care Unit required ventilation. Risk factors associated with ventilation included a younger mean age, female sex, low birthweight, failure to thrive and the presence of an underlying illness. Ventilated patients were also more likely to have a higher respiratory distress assessment index (RDAI) score, pneumonic infiltration on chest X-ray, lower serum sodium and a positive respiratory syncytial virus isolation in the tracheal secretion.

Paediatric intensive care in Malaysia is a developing subspecialty with an increasing number of specialists with a paediatric background being involved in the care of critically ill children. A part prospective and part retrospective review of 118 consecutive non-neonatal ventilated patients in University Hospital, Kuala Lumpur was carried out from 1 June 1995 to 31 December 1996 to study the clinical epidemiology and outcome in our paediatric intensive case unit (PICU). The mean age of the patients was 33.9 +/- 6.0 months (median 16 months). The main mode of admission was emergency (96.6 per cent) with an overall mortality rate of 42 per cent (50/118). The mean paediatric risk of mortality (PRISM) score was 20 +/- 0.98 SEM, with 53 per cent of patients having a score of over 30 per cent. Multiorgan dysfunction (MODS) was identified in 71 per cent of patients. Admission efficiency (mortality risk > 1 per cent) was 97 per cent. Standardized mortality rate using PRISM was an acceptable 1.06. The main diagnostic categories were respiratory (32 per cent), neurology (22 per cent), haematology-oncology (18 per cent); the aetiology of dysfunction was mainly infective. Non-survivors were older (29.5 vs. 13.8 months, p < 0.0001), had more severe illness (mean PRISM score 30 vs. 14, p < 0.0001), were more likely to develop MODS (96 vs. 53 per cent, p < 0.0001) and required more intervention and monitoring. Paediatric intensive care in Malaysia differs widely from that in developed countries in patient characteristics, severity of illness, and care modalities provided.

Severe bronchiolitis requiring mechanical ventilation is uncommon and is associated with the risk of barotrauma. We report our experience with 25 (42%) of 60 infants admitted to the Paediatric Intensive Care Unit (PICU) with severe bronchiolitis who required mechanical ventilation. Eighteen patients (72%) had severe hypoxaemia (PaO2/FiO2 < 250). The mean airway pressure required ranged from 5.8 to 15.6 cmH2O with median ventilation duration of 4.0 days (range 2.0-14.0 days). Oxygenation improved significantly within 12 hours of intubation. There was only one death. Mechanical ventilation is required in a subset of patients for severe bronchiolitis and is effective and generally well tolerated.

Objectives: To compare the modes of death and factors leading to withdrawal or limitation of life support in a paediatric intensive care unit (PICU) in a developing country., Methods: Retrospective analysis of all children (< 12 years) dying in the PICU from January 1995 to December 1995 and January 1997 to June 1998 (n = 148)., Results: The main mode of death was by limitation of treatment in 68 of 148 patients, failure of active treatment including cardiopulmonary resuscitation in 61, brain death in 12, and withdrawal of life support with removal of endotracheal tube in seven. There was no significant variation in the proportion of limitation of treatment, failure of active treatment, and brain death between the two periods; however, there was an increase in withdrawal of life support from 0% in 1995 to 8% in 1997-98. Justification for limitation was based predominantly on expectation of imminent death (71 of 75). Ethnic variability was noted among the 14 of 21 patients who refused withdrawal. Discussions for care restrictions were initiated almost exclusively by paediatricians (70 of 75). Diagnostic uncertainty (36% v 4.6%) and presentation as an acute illness were associated with the use of active treatment., Conclusions: Limitation of treatment is the most common mode of death in a developing country's PICU and active withdrawal is still not widely practised. Paediatricians in developing countries are becoming more proactive in managing death and dying but have to consider sociocultural and religious factors when making such decisions.

During an outbreak of hand-foot-mouth disease caused by enterovirus 71 (EV-71) in 1997, 4 children presented with sudden cardiopulmonary collapse and minimal neurologic features. All children received cardiopulmonary resuscitation but died within a few hours of admission. Postmortem studies showed infection by EV-71 with extensive damage to the medulla and pons. We postulate an etiologic link between EV-71 and brainstem encephalomyelitis as the cause of pulmonary edema and death.

An 18-month analysis of 52 percutaneously placed central venous catheters in 48 critically ill children was done. Success rate were 91.7% (33/36) and 93.8% (15/16) for femoral and non-femoral catheters respectively. Presence of hypotension (48.1%) and significant coagulopathy (26.9%) did not affect the success rate significantly. Minor bleeding and venous congestion was seen in 5.5% (2/36) of patients with femoral catheters. Infections were found in 2.7% (1/36) of femoral and 6.6% (1/15) of non-femoral catheters. The low incidence of complications and the relative ease of insertion makes the femoral route the preferred site for trainee medical officers in critically ill children when central access is indicated.