Rina Triasih

Maternal antibodies to rotavirus: could they interfere with live rotavirus vaccines in developing countries?

INTRODUCTION Past experience with live oral vaccines including licensed rotavirus vaccines demonstrates a trend towards reduced vaccine efficacy in developing countries compared with developed countries. The reasons behind this disparity are not well understood. Transplacental transfer of maternal antibodies and breast milk ingestion may attenuate vaccine responses in infants in developing countries where rotavirus infections are endemic, and maternal antibody levels are high. We examined the prevalence and level of rotavirus antibody in maternal and cord serum, colostrum and breast milk in a developing country setting. METHODS 100 mother-infant pairs were prospectively recruited from December 2008 to February 2009 at Dr. Sardjito Hospital, Yogyakarta, Indonesia. Maternal and cord sera were collected during delivery. Colostrum and transitional breast milk were collected between day 0-3 and day 7-10 postpartum respectively. Rotavirus-specific IgA and IgG were estimated for all specimens and virus neutralization assays were conducted on a subset of milk specimens. RESULTS All maternal and cord serum samples were positive for rotavirus-specific IgG antibodies with a strong correlation between levels of rotavirus-specific IgG in mothers and levels transferred to infants in cord blood (r=0.86; p=0.001). 78% of colostrum and 67% of transitional breast milk specimens were positive for rotavirus-specific IgA. There was a median 4-fold decrease in rotavirus-specific IgA from colostrum to transitional breast milk. Neutralizing antibodies were present in 56% of colostrum specimens assayed (19/34) and in 41% of transitional milk specimens assayed (14/34). CONCLUSIONS Maternal serum and breast milk antibodies to rotavirus are highly prevalent in a developing country setting. Evaluation of the impact of maternal anti-rotavirus serum and breast milk antibody upon vaccine immunogenicity would help to inform rotavirus vaccination strategies, especially in developing settings.

A Prospective Evaluation of the Symptom-Based Screening Approach to the Management of Children Who Are Contacts of Tuberculosis Cases

BACKGROUND Child tuberculosis contact screening and management can enhance case finding and prevent tuberculosis disease. It is universally recommended but rarely implemented in tuberculosis-endemic settings. The World Health Organization (WHO)-recommended symptom-based screening approach could improve implementation but has not been prospectively evaluated. METHODS We conducted a cohort study of children who were close contacts of pulmonary tuberculosis patients in Indonesia from August 2010 to December 2012. We performed clinical assessment, tuberculin skin test, and chest radiography in all eligible children irrespective of symptoms at baseline. Mycobacterial culture and Xpert MTB/RIF assay were performed on sputum from children with persistent symptoms of suspected tuberculosis. Children were managed according to WHO guidelines and were prospectively followed for 12 months. RESULTS A total of 269 child contacts of 140 index cases were evaluated. At baseline, 21 (8%) children had tuberculosis diagnosed clinically; an additional 102 (38%) had evidence of infection without disease. Of children with any tuberculosis-related symptoms at baseline, 21% had tuberculosis diagnosed compared with none of the asymptomatic children (P < .001). After 12 months of follow-up, none of the 99 eligible young child contacts (<5 years) who received isoniazid preventive therapy (IPT) had developed disease compared with 4 of 149 (2.6%) asymptomatic older children who did not receive IPT. CONCLUSIONS Symptom-based screening is an effective and simple approach to child tuberculosis contact management that can be implemented at the primary healthcare level.

Preventive therapy in children exposed to Mycobacterium tuberculosis: problems and solutions.

Young children living with a tuberculosis patient are at high risk of Mycobacterium tuberculosis infection and disease. WHO guidelines promote active screening and isoniazid (INH) preventive therapy (PT) for such children under 5 years, yet this well‐established intervention is seldom used in endemic countries. We review the literature regarding barriers to implementation of PT and find that they are multifactorial, including difficulties in screening, poor adherence, fear of increasing INH resistance and poor acceptability among primary caregivers and healthcare workers. These barriers are largely resolvable, and proposed solutions such as the adoption of symptom‐based screening and shorter drug regimens are discussed. Integrated multicomponent and site‐specific solutions need to be developed and evaluated within a public health framework to overcome the policy–practice gap and provide functional PT programmes for children in endemic settings.

Contact Investigation of Children Exposed to Tuberculosis in South East Asia: A Systematic Review

Background. Screening of children who are household contacts of tuberculosis (TB) cases is universally recommended but rarely implemented in TB endemic setting. This paper aims to summarise published data of the prevalence of TB infection and disease among child contacts in South East Asia. Methods. Search strategies were developed to identify all published studies from South East Asia of household contact investigation that included children (0–15 years). Results. Eleven studies were eligible for review. There was heterogeneity across the studies. TB infection was common among child contacts under 15 years of age (24.4–69.2%) and was higher than the prevalence of TB disease, which varied from 3.3% to 5.5%. Conclusion. TB infection is common among children that are household contacts of TB cases in South East Asia. Novel approaches to child contact screening and management that improve implementation in South East Asia need to be further evaluated.

Prevention of nosocomial infections in developing countries, a systematic review.

Abstract Background: Prevention of nosocomial infection is key to providing good quality, safe healthcare. Infection control programmes (hand-hygiene campaigns and antibiotic stewardship) are effective in reducing nosocomial infections in developed countries. However, the effectiveness of these programmes in developing countries is uncertain. Objective: To evaluate the effectiveness of interventions for preventing nosocomial infections in developing countries. Methods: A systematic search for studies which evaluated interventions to prevent nosocomial infection in both adults and children in developing countries was undertaken using PubMed. Only intervention trials with a randomized controlled, quasi-experimental or sequential design were included. Where there was adequate homogeneity, a meta-analysis of specific interventions was performed using the Mantel–Haenzel fixed effects method to estimate the pooled risk difference. Results: Thirty-four studies were found. Most studies were from South America and Asia. Most were before-and-after intervention studies from tertiary urban hospitals. Hand-hygiene campaigns that were a major component of multifaceted interventions (18 studies) showed the strongest effectiveness for reducing nosocomial infection rates (median effect 49%, effect range 12·7–100%). Hand-hygiene campaigns alone and studies of antibiotic stewardship to improve rational antibiotic use reduced nosocomial infection rates in three studies [risk difference (RD) of −0·09 (95%CI −0·12 to −0·07) and RD of −0·02 (95%CI −0·02 to −0·01), respectively]. Conclusions: Multifaceted interventions including hand-hygiene campaigns, antibiotic stewardship and other elementary infection control practices are effective in developing countries. The modest effect size of hand-hygiene campaigns alone and negligible effect size of antibiotic stewardship reflect the limited number of studies with sufficient homogeneity to conduct meta-analyses.

Outcomes following admission to intensive care for asthma

Objective Acute severe asthma in children is a common cause of admission to intensive care units (ICU), but there are few reports on long-term outcomes. This study describes outcomes for children with asthma admitted to an ICU. Methods All children with asthma aged 2–18 years admitted to the ICU at the Royal Childrens Hospital Melbourne between 1990 and 2004 were eligible for the study. Data were collected by reviewing medical records and through telephone interviews. Results Complete data were obtained for 410 (61%) of 684 eligible patients. The mean duration of follow-up was 10.3±4.6 years. After the index admission, 67% were readmitted to hospital for asthma and 17% to the ICU. Eighty-eight per cent continued to have asthma: 46% had episodic asthma and 42% persistent asthma. Twelve patients (1.8%) subsequently died from asthma. Five per cent of those who required ventilation at their index admission died within 10 years. Risk factors for ICU readmission were admission for asthma in the preceding year (AOR 4.7; 95% CI 2.4 to 9.3) and ventilation at admission (AOR 2.4; 95% CI 1.0 to 5.3). Risk factors for subsequent mortality were multiple ICU admissions (AOR 5.0; 95% CI 1.3 to 19), persistent asthma (AOR 5.8; 95% CI 1.2 to 28.5) and ventilation at admission (AOR 4.5; 95% CI 1.3 to 15.7). Conclusion Admission to the ICU for asthma is a predictor of hospital readmission. Those with persistent asthma or requiring ventilation are at significant risk of mortality in subsequent years and require close follow-up.

Wavelet Augmented Cough Analysis for Rapid Childhood Pneumonia Diagnosis

Pneumonia is the cause of death for over a million children each year around the world, largely in resource poor regions such as sub-Saharan Africa and remote Asia. One of the biggest challenges faced by pneumonia endemic countries is the absence of a field deployable diagnostic tool that is rapid, low-cost and accurate. In this paper, we address this issue and propose a method to screen pneumonia based on the mathematical analysis of cough sounds. In particular, we propose a novel cough feature inspired by wavelet-based crackle detection work in lung sound analysis. These features are then combined with other mathematical features to develop an automated machine classifier, which can separate pneumonia from a range of other respiratory diseases. Both cough and crackles are symptoms of pneumonia, but their existence alone is not a specific enough marker of the disease. In this paper, we hypothesize that the mathematical analysis of cough sounds allows us to diagnose pneumonia with sufficient sensitivity and specificity. Using a bedside microphone, we collected 815 cough sounds from 91 patients with respiratory illnesses such as pneumonia, asthma, and bronchitis. We extracted wavelet features from cough sounds and combined them with other features such as Mel Cepstral coefficients and non-Gaussianity index. We then trained a logistic regression classifier to separate pneumonia from other diseases. As the reference standard, we used the diagnosis by physicians aided with laboratory and radiological results as deemed necessary for a clinical decision. The methods proposed in this paper achieved a sensitivity and specificity of 94% and 63%, respectively, in separating pneumonia patients from non-pneumonia patients based on wavelet features alone. Combining the wavelets with features from our previous work improves the performance further to 94% and 88% sensitivity and specificity. The performance far surpasses that of the WHO criteria currently in common use in resource-limited settings.

Cough Sound Analysis Can Rapidly Diagnose Childhood Pneumonia

Pneumonia annually kills over 1,800,000 children throughout the world. The vast majority of these deaths occur in resource poor regions such as the sub-Saharan Africa and remote Asia. Prompt diagnosis and proper treatment are essential to prevent these unnecessary deaths. The reliable diagnosis of childhood pneumonia in remote regions is fraught with difficulties arising from the lack of field-deployable imaging and laboratory facilities as well as the scarcity of trained community healthcare workers. In this paper, we present a pioneering class of technology addressing both of these problems. Our approach is centred on the automated analysis of cough and respiratory sounds, collected via microphones that do not require physical contact with subjects. Cough is a cardinal symptom of pneumonia but the current clinical routines used in remote settings do not make use of coughs beyond noting its existence as a screening-in criterion. We hypothesized that cough carries vital information to diagnose pneumonia, and developed mathematical features and a pattern classifier system suited for the task. We collected cough sounds from 91 patients suspected of acute respiratory illness such as pneumonia, bronchiolitis and asthma. Non-contact microphones kept by the patient’s bedside were used for data acquisition. We extracted features such as non-Gaussianity and Mel Cepstra from cough sounds and used them to train a Logistic Regression classifier. We used the clinical diagnosis provided by the paediatric respiratory clinician as the gold standard to train and validate our classifier. The methods proposed in this paper could separate pneumonia from other diseases at a sensitivity and specificity of 94 and 75% respectively, based on parameters extracted from cough sounds alone. The inclusion of other simple measurements such as the presence of fever further increased the performance. These results show that cough sounds indeed carry critical information on the lower respiratory tract, and can be used to diagnose pneumonia. The performance of our method is far superior to those of existing WHO clinical algorithms for resource-poor regions. To the best of our knowledge, this is the first attempt in the world to diagnose pneumonia in humans using cough sound analysis. Our method has the potential to revolutionize the management of childhood pneumonia in remote regions of the world.

Editorial Commentary: More Evidence to Support Screening of Child Contacts of Tuberculosis Cases: If Not Now, Then When?

Evidence Q2 that informs the rationale for 10 screening of children who are close contacts of a case of tuberculosis and for providing preventive therapy for this high-risk group has been available for >50 years [1, 2]. The policy is almost universally accepted, being 15 included in global and almost all national tuberculosis control program guidelines [3]. However, in practice it is rarely implemented except in low-tuberculosis-burden, resource-rich settings [4]. Contact screening 20 has 2 main roles. One is to identify at-risk contacts such as young or human immunodeficiency virus (HIV)–infected children who require preventive therapy. The other is to identify contacts of any age who have 25 tuberculosis, that is, active, case finding. In this issue of Clinical Infectious Diseases, Jaganath et al [5] provide additional compelling evidence from a well-conducted study of the potential of contact investiga30 tion as a public health intervention in a tuberculosis-endemic and resource-limited setting. Although the findings are largely consistent with previous studies, there are features worth highlighting that make this an important study. It is a large prospective study reporting 761 Ugandan children who were household contacts of an adult with tuberculosis, and half of the contacts were young children (aged <5 years). Case definitions were clearly defined, and contacts were carefully evaluated, including samples for culture taken from those with symptoms or suggestive radiological findings, thereby strengthening diagnostic certainty. Furthermore, the cohort was followed for 2 years, providing important outcome data that are not available from the many previous cross-sectional studies that have reported a high prevalence of infection with Mycobacterium tuberculosis in child contacts [6, 7]. Tuberculosis was diagnosed in 10% of child contacts. This represents a higher prevalence than is usually reported [6, 7] but cannot be dismissed as simply overdiagnosis given that the majority (71%) of cases were culture confirmed. Diagnostic yield from culture was 4-fold higher than from smear and, as expected, tuberculosis was significantly more common in the young children. The prevalence of disease in the young child contacts was extremely high, equivalent to 16 400 per 100 000 young child contacts. Active case finding identified 79 children with tuberculosis who had not been diagnosed previously. These data provide strong support for case finding in this high-risk age group. 35 Moreover, this age group is still poorly represented by recording and reporting practices in many endemic settings. A tuberculin test was positive at baseline in 63% of child contacts without disease, 40 at the upper range of infection prevalence reported previously [6, 7]. Isoniazid preventive therapy (IPT) is very effective in preventing disease in these children [1, 8] but is rarely implemented in tuberculosis45 endemic settings, and, when implemented, uptake and adherence are often poor. In this study, 74% of eligible contacts completed at least 6 months of IPT. Only 2 (<1%) children developed tuberculosis 50 while receiving IPT and 1 after completion. This is a very positive outcome and an important observation strengthened by the 2 years of follow-up. The efficacy of IPT in this population cannot be deter55 mined from this study, but this finding supports the benefit of IPT for child contacts. The main characteristics that were identified for disease were young age, HIV 60 infection, and lack of a BCG scar. The increased risk for HIV-infected children is well established, and IPT is recommended for HIV-infected contacts irrespective of age once disease is excluded [3]. A recent 65 study from Tanzania reported an additional protective effect of antiretroviral therapy Received 22 August 2013; accepted 23 August 2013. Correspondence: Stephen M. Graham, PhD, FRACP, Centre for International Child Health, The University of Melbourne Department of Paediatrics, Royal Children’s Hospital, Flemington Road, Parkville, VIC 3052, Australia (steve.graham@rch. org.au). Clinical Infectious Diseases

Understanding Market Size and Reporting Gaps for Paediatric TB in Indonesia, Nigeria and Pakistan: Supporting Improved Treatment of Childhood TB in the Advent of New Medicines.

Objective of the Study We sought to understand gaps in reporting childhood TB cases among public and private sector health facilities (dubbed “non-NTP” facilities) outside the network of national TB control programmes, and the resulting impact of under-reporting on estimates of paediatric disease burden and market demand for new medicines. Methodology Exploratory assessments were carried out in Indonesia, Nigeria and Pakistan, reaching a range of facility types in two selected areas of each country. Record reviews and interviews of healthcare providers were carried out to assess numbers of unreported paediatric TB cases, diagnostic pathways followed and treatment regimens prescribed. Main Findings A total of 985 unreported diagnosed paediatric TB cases were identified over a three month period in 2013 in Indonesia from 64 facilities, 463 in Pakistan from 35 facilities and 24 in Nigeria from 20 facilities. These represent an absolute additional annualised yield to 2013 notifications reported to WHO of 15% for Indonesia, 2% for Nigeria and 7% for Pakistan. Only 12% of all facilities provided age and sex-disaggregated data. Findings highlight the challenges of confirming childhood TB. Diagnosis patterns in Nigeria highlight a very low suspicion for childhood TB. Providers note the need for paediatric medicines aligned to WHO recommendations. Conclusion: How Market Data Can Support Better Public Health Interventions This study emphasises the impact of incomplete reporting on the estimation of disease burden and potential market size of paediatric TB medicines. Further studies on “hubs” (facilities treating large numbers of childhood TB cases) will improve our understanding of the epidemic, support introduction efforts for new treatments and better measure markets for new paediatric medicines.