Aetiology Of Neonatal Infection In South Asia Research Articles

Neurodevelopmental outcomes following possible serious bacterial infection in early infancy in Karachi, Pakistan: a prospective cohort study

BackgroundPakistan reports a significant burden of neonatal mortality, with infections as one of the major causes. We aim to assess the long-term impact of early infancy infections on neurodevelopmental outcomes during later childhood.MethodsWe conducted a prospective follow-up study of the cohort enrolled at the Karachi site of the Aetiology of Neonatal Infection in South Asia (ANISA) during 2019–2020. Children with a possible serious bacterial infection (based on the WHO IMCI algorithm) at early infancy were assessed for neurodevelopment at 6–9 years of age and compared with healthy controls. The Ten Questions (TQS) questionnaire, Strengths and Difficulties Questionnaire (SDQ), and Parent’s Evaluation of Developmental Stage Assessment Level (PEDS: DM-AL) neurodevelopmental assessment tools, were administered and scored by the research staff who were blinded to the child’s exposure status. Generalized Structural Equation Modelling (GSEM) was employed to verify relationships and associations among developmental milestones, anthropometry, and sociodemographic variables.ResultsA total of 398 children (241 cases and 157 controls) completed neurodevelopmental and growth assessments. Cases had a significantly higher rate of abnormal TQS scores (54.5% vs. 35.0%, p-value 0.001), greater delays in motor milestones (21.2% vs. 12.1%, p-value 0.02), lower fine motor skills (78.4 ± 1.4 vs. 83.2 ± 1.5, p-value 0.02). The receptive language skills were well-developed in both groups. According to the logistic regression model, exposure to infection during the first 59 days of life was associated with delayed TQS milestones (β = -0.6, 95% CI -1.2,-0.04), TQS hearing domain (β = -0.3, 95% CI: -1.2 to 0.7), PEDS: DM-AL fine motor domain (β = -1.3, 95% CI: -4.4 to 1.7), PEDS: DM-AL receptive language development (β = -1.1, 95% CI: -3.7 to 1.4) and child anthropometric measurements such as weight and height (β = -0.2, 95% CI: -0.4 to 0.01 and β = -0.2, 95% CI: -0.4 to -0.01, respectively). Early pSBI exposure was positively associated with PEDS: DM-AL self-help domain (β = 0.6, 95% CI: -1.2 to 2.4) and SDQ-P overall score (β = 0.02, 95% CI: -0.3 to 0.3).ConclusionChildren exposed to PSBI during early infancy have higher rates of abnormal development, motor delays, and lower fine motor skills during later childhood in Pakistan. Socioeconomic challenges and limited healthcare access contribute to these challenges, highlighting the need for long-term follow-ups with integrated neurodevelopment assessments.

Community-based asthma assessment in young children: adaptations for a multicentre longitudinal study in South Asia.

Background:Systematic assessment of childhood asthma is challenging in low- and middle-income country (LMIC) settings due to the lack of standardised and validated methodologies. We describe the contextual challenges and adaptation strategies in the implementation of a community-based asthma assessment in four resource-constrained settings in Bangladesh, India, and Pakistan.Method:We followed a group of children of age 6–8 years for 12 months to record their respiratory health outcomes. The study participants were enrolled at four study sites of the ‘Aetiology of Neonatal Infection in South Asia (ANISA)’ study. We standardised the research methods for the sites, trained field staff for uniform data collection and provided a ‘Child Card’ to the caregiver to record the illness history of the participants. We visited the children on three different occasions to collect data on respiratory-related illnesses. The lung function of the children was assessed in the outreach clinics using portable spirometers before and after 6-minute exercise, and capillary blood was examined under light microscopes to determine eosinophil levels.Results:We enrolled 1512 children, 95.5% (1476/1512) of them completed the follow-up, and 81.5% (1232/1512) participants attended the lung function assessment tests. Pre- and post-exercise spirometry was performed successfully in 88.6% (1091/1232) and 85.7% (1056/1232) of children who attempted these tests. Limited access to health care services, shortage of skilled human resources, and cultural diversity were the main challenges in adopting uniform procedures across all sites. Designing the study implementation plan based on the local contexts and providing extensive training of the healthcare workers helped us to overcome these challenges.Conclusion:This study can be seen as a large-scale feasibility assessment of applying spirometry and exercise challenge tests in community settings of LMICs and provides confidence to build capacity to evaluate children’s respiratory outcomes in future translational research studies.

Centralized Data Management in a Multicountry, Multisite Population-based Study.

A centralized data management system was developed for data collection and processing for the Aetiology of Neonatal Infection in South Asia (ANISA) study. ANISA is a longitudinal cohort study involving neonatal infection surveillance and etiology detection in multiple sites in South Asia. The primary goal of designing such a system was to collect and store data from different sites in a standardized way to pool the data for analysis. We designed the data management system centrally and implemented it to enable data entry at individual sites. This system uses validation rules and audit that reduce errors. The study sites employ a dual data entry method to minimize keystroke errors. They upload collected data weekly to a central server via internet to create a pooled central database. Any inconsistent data identified in the central database are flagged and corrected after discussion with the relevant site. The ANISA Data Coordination Centre in Dhaka provides technical support for operations, maintenance and updating the data management system centrally. Password-protected login identifications and audit trails are maintained for the management system to ensure the integrity and safety of stored data. Centralized management of the ANISA database helps to use common data capture forms (DCFs), adapted to site-specific contextual requirements. DCFs and data entry interfaces allow on-site data entry. This reduces the workload as DCFs do not need to be shipped to a single location for entry. It also improves data quality as all collected data from ANISA goes through the same quality check and cleaning process.

Implementation of the ANISA Protocol in Sylhet, Bangladesh: Challenges and Solutions.

Despite the high rate of deaths in young infants (0-59 days) attributable to infections in resource-poor countries, data on bacterial and viral etiologies of community-acquired infections in this age group are limited. These data are needed to develop appropriate preventive strategies and suitable antibiotic treatment regimens for reducing the number of young infant deaths from infections. The Aetiology of Neonatal Infection in South Asia (ANISA) study is designed to generate these critical data and is being implemented in Bangladesh, India and Pakistan. The Sylhet site in Bangladesh was selected because neonatal mortality is high in this country and particularly in Sylhet District. In this article, we describe the contextual challenges in implementing the ANISA study in Sylhet, as well as the strategies developed by our team to address these challenges. The major challenge in implementing the ANISA protocol in Sylhet is conducting the first postnatal visit within 24 hours of birth. This problem stems from several social, cultural and geographical characteristics of the study population and its demographic profile. In this area, most births take place at home, referral compliance for newborn illness to health facilities is low and the blood culture contamination rate is high. Community mobilization, cellphone-based birth notification by families, delivery of quality services at study hospitals and referral support to families in need were some of the strategies adopted by the Sylhet site team for overcoming these challenges during study implementation. Quality control in specimen collection, transportation and processing also plays a role in ensuring satisfactory performance. Our research team, with support from the ANISA coordination center, has successfully addressed these challenges and is implementing the study protocol while maintaining the high quality benchmark set by the coordination center.

Methods Employed in Monitoring and Evaluating Field and Laboratory Systems in the ANISA Study: Ensuring Quality.

The Aetiology of Neonatal Infection in South Asia (ANISA) study maintains operations in Bangladesh, India and Pakistan. We developed and deployed a multilayered monitoring system to measure performance indicators of field sites and laboratory operations. This system allows for real-time provision of feedback to study site teams and project stakeholders. The goal of this monitoring and evaluation system is to promote optimal performance and consistency in protocol application at all sites over the course of the study, thereby safeguarding the validity of project findings. This article describes each of the interdependent monitoring layers that were conceptualized, developed and employed by the ANISA coordination team. Layers of monitoring include site-level, central and database-related activities along with periodic site visitation. We provide a number of real-world examples of how feedback from the ANISA monitoring system directly informs a number of crucial decisions and course corrections during the project. The ANISA monitoring system represents a transparent, understandable and practical resource for development of project monitoring systems in complex multisite health research projects.

Implementation of the ANISA Study in Karachi, Pakistan: Challenges and Solutions.

Aetiology of Neonatal Infection in South Asia (ANISA) is a multicenter study in Bangladesh, India and Pakistan exploring the incidence and etiology of neonatal infections. A periurban site in Karachi was selected for its representativeness of the general population in neonatal health indicators. An established demographic surveillance system and other infrastructure needed for conducting the study already existed at this site. ANISA presents a unique challenge because of the need to capture every birth outcome in the community within a few hours of delivery to reliably estimate the incidence and etiology of early-onset sepsis in a setting where home births and deaths are common. Major challenges at the Karachi site are related to early birth reporting and newborn assessment for births outside the catchment areas, parental refusal to participate, diverse ethnicity of the population, collection of biological specimens from healthy controls, political instability and crime, power outages and blood culture contamination. Some of the remedial actions taken include prolonging working hours; developing counseling skills of field workers; hiring staff with different linguistic abilities from within the study community; liaising with health facilities, key community informants, Lady Health Workers and traditional birth attendants; hiring community mobilizers; enhancing community sensitization; developing contingency plans for field work interruptions and procuring backup generators. The specimen contamination rate has decreased through training, supervision and video monitoring of blood collection procedures with individualized counseling of phlebotomists. ANISA offers lessons for successful implementation of complex study protocols in areas of high child mortality and challenging social environments.

Classification of Blood Culture Isolates Into Contaminants and Pathogens on the Basis of Clinical and Laboratory Data.

The multisite community-based study, Aetiology of Neonatal Infection in South Asia (ANISA), uses blood culture as the gold standard for identifying the etiology of neonatal infection. Considering the importance of this age-old diagnostic tool and the risk of contamination, ANISA has employed rigorous measures to prevent contamination at all stages of blood collection, processing and culture. Because contamination may still occur, an independent expert group evaluates the routinely collected clinical and laboratory data to determine whether a blood culture isolate is a contaminant or a true pathogen. This article describes the methodology used by ANISA to determine whether a blood culture isolate is likely to be a true pathogen or a contaminant in neonatal sepsis.

Challenges in Implementation of ANISA Protocol at the Vellore Site, India.

The Aetiology of Neonatal Infection in South Asia (ANISA) study aims to determine the population-based incidence, etiology, risk factors and antibiotic resistance profiles of community-acquired young infant infections in Bangladesh, India and Pakistan using community-based surveillance and standard newer diagnostic tests. The data generated will help plan preventive and treatment strategies to reduce neonatal and infant mortality in this region. The aim of this article is to describe the site-specific characteristics, challenges and solutions in implementing the ANISA protocol at the Vellore site, India. Vellore joined the ANISA study 2 years after the sites in Bangladesh and Pakistan, and some challenges relate to the need for rapid implementation. The Vellore site differs primarily in the high rate of institutional deliveries, actively promoted by the Government of India's conditional cash transfer program. The Vellore site hospitals are regular care providers for the study population, which leads to very high rates of consent for enrollment and collection of samples. Keeping blood culture contamination rates low was a challenge the site team overcame by adhering strictly to the protocol. Issues related to incorporation of a large study into a busy clinical services laboratory were overcome by meticulously setting up algorithms related to receipt, processing and storage of samples. ANISA is a complex study, but the challenges in implementation have been largely resolved and documented.

Laboratory Methods for Determining Etiology of Neonatal Infection at Population-based Sites in South Asia: The ANISA Study.

The Aetiology of Neonatal Infection in South Asia (ANISA) study aims to determine the etiology of neonatal infections in 5 population-based sites in Bangladesh, India and Pakistan. The main laboratory challenges in ANISA were selection and consistent implementation of laboratory methods at participating sites with varied infrastructure. The other specific challenges included (1) specimen collection and transport to designated study laboratories and timely processing in rural settings; (2) minimal or nonexistent laboratory facilities at the field sites; (3) obtaining sufficient volumes of blood from enrolled infants aged 0-59 days and (4) caregivers' concerns about collection of clinical specimens from young infants. An additional challenge was selecting an appropriate molecular platform from multiple available options, all with limited field validation, for use in determining infection in young infants. This article describes how the challenges of specimen collection, transport and processing and implementation of laboratory methods have been addressed in the ANISA study. It also describes the measures taken to improve detection of microorganisms causing young infant infections by enhancing the sensitivity of existing laboratory methods for pathogen detection.

Infection Surveillance Protocol for a Multicountry Population-based Study in South Asia to Determine the Incidence, Etiology and Risk Factors for Infections Among Young Infants of 0 to 59 Days Old.

Insufficient knowledge of the etiology and risk factors for community-acquired neonatal infection in low-income countries is a barrier to designing appropriate intervention strategies for these settings to reduce the burden and treatment of young infant infection. To address these gaps, we are conducting the Aetiology of Neonatal Infection in South Asia (ANISA) study among young infants in Bangladesh, India and Pakistan. The objectives of ANISA are to establish a comprehensive surveillance system for registering newborns in study catchment areas and collecting data on bacterial and viral etiology and associated risk factors for infections among young infants aged 0-59 days. We are conducting active surveillance in 1 peri-urban and 4 rural communities. During 2 years of surveillance, we expect to enroll an estimated 66,000 newborns within 7 days of their birth and to follow-up them until 59 days of age. Community health workers visit each young infant in the study area 3 times in the first week of life and once a week thereafter. During these visits, community health workers assess the newborns using a clinical algorithm and refer young infants with signs of suspected infection to health care facilities where study physicians reassess them and provide care if needed. On physician confirmation of suspected infection, blood and respiratory specimens are collected and tested to identify the etiologic agent. ANISA is one of the largest initiatives ever undertaken to understand the etiology of young infant infection in low-income countries. The data generated from this surveillance will help guide evidence-based decision making to improve health care in similar settings.

Aetiology of Neonatal Infection in South Asia (ANISA): An Initiative to Identify Appropriate Program Priorities to Save Newborns.

Aetiology of Neonatal Infection in South Asia (ANISA): An Initiative to Identify Appropriate Program Priorities to Save Newborns.

Challenges in Implementation of the ANISA Protocol at the Matiari Site, Pakistan.

The Aetiology of Neonatal Infection in South Asia (ANISA) study is a population-based study with sites in Bangladesh, India and Pakistan. It aims to determine community-acquired incidence, etiology and associated risk factors for neonatal infections. Matiari, a rural site in Pakistan, was chosen for the study due to its high neonatal mortality rate and the presence of an established pregnancy and birth surveillance system. This article summarizes various challenges, remedial measures taken and lessons learned during the implementation of the ANISA study protocol in the unique rural setting of Matiari where the majority of births take place at home and accessibility to health care is limited. Achieving and maintaining project targets of early registration of birth and collection of biological specimens in households have been challenging in Matiari. Capturing births of study subjects that occur outside the catchment areas and those taking place during public holidays and acquiring parental consent for specimen collection from healthy controls require extensive community mobilization. Contamination and power outages that affect the laboratory equipment are 2 of the major logistic challenges faced. We keep track of pregnancy outcomes through mobile phones and reimburse the costs for birth notifications to the caller. We created separate dedicated mobile teams that visit newborns outside the catchment area and carry out possible serious bacterial infection assessments. We also formed mobile teams for specimen collection from residences of newborns as there is no facility for specimen collection at this site. Our study personnel work on holidays and weekends to improve the study's performance. We nurture strong community liaison by employing staff from within the community. We train the study physicians on communication and counseling skills required for overcoming refusal for referral and specimen collection. The contamination rate is controlled by repeated training and supervision and extensive monitoring of phlebotomy activities. The majority of phlebotomy procedures are recorded on video in the field to provide feedback to phlebotomists for improving their performance. The contextual challenges faced in field implementation of the ANISA protocol in the rural setting of Matiari are unique. These challenges are being successfully addressed through hard work, strict monitoring and improvisation. This experience can be used for improving study performance in similar settings elsewhere.

Challenges in Implementation of the ANISA Protocol at the Odisha Site in India.

The Aetiology of Neonatal Infection in South Asia (ANISA) study is being carried out at 5 sites across Bangladesh, India and Pakistan, generating in-depth information on etiologic agents in the community setting. Pregnancies are identified, births are registered and young infants are followed up to 59 days old with regular assessments for possible serious bacterial infection following a generic protocol. Specimens are collected from suspected cases. This article describes the challenges in implementing the generic ANISA protocol and modifications made to accommodate the Odisha site, India. Primary challenges in implementing the protocol are the large geographic area, with a population of over 350,000, to be covered; assessing young infants at home and arranging timely transport of sick young infants to study hospitals for physician confirmation of illness; and specimen collection and treatment. A large workforce is deployed in a 3-tier system in the field, while clinical, microbiology, laboratory and data management teams collaborate dynamically. Mobile phones with text message capability, integration with the Odisha State government's health system, involvement of local communities and strict monitoring at different levels have been critical in addressing these challenges. This article describes the challenges and modalities adopted to collect complex and accurate data on etiology, timing of disease and associated factors for community-acquired neonatal infections. Attention to local culture and customs, training and employing community level workers and supervisors, involving existing government machinery, using technology (cell phones), and uninterrupted systematic monitoring are critical for implementing such complex protocols that aim to collect population-based data to drive policy.

Using Text Messages for Critical Real-time Data Capture in the ANISA Study.

The Aetiology of Neonatal Infection in South Asia (ANISA) study takes advantage of text messaging technology to record information required for randomizing the study population into a control subcohort. The text message system is also used for monitoring various study activities. When a child-health worker registers a newborn in the study, she sends a text message to a database server containing the study identification number and newborn's age at the time of registration. For each possible serious bacterial infection case, a study physician also sends a text message to the same server with the age of the young infant at the time of illness assessment. Using this information, a computer-based algorithm randomizes the newborn into a control subcohort. Text messages are also sent to alert the study physicians and study supervisors of a possible serious bacterial infection case being referred to health-care facilities. Phlebotomists working at remote specimen collection sites send text messages to the site laboratory personnel before sending the specimens through porters. Real-time data entry and monitoring are challenging for any population-based study conducted in remote areas. Our text messaging system provides an opportunity to overcome this barrier where availability of data entry facilities is limited.

Optimization of Multiple Pathogen Detection Using the TaqMan Array Card: Application for a Population-Based Study of Neonatal Infection

Identification of etiology remains a significant challenge in the diagnosis of infectious diseases, particularly in resource-poor settings. Viral, bacterial, and fungal pathogens, as well as parasites, play a role for many syndromes, and optimizing a single diagnostic system to detect a range of pathogens is challenging. The TaqMan Array Card (TAC) is a multiple-pathogen detection method that has previously been identified as a valuable technique for determining etiology of infections and holds promise for expanded use in clinical microbiology laboratories and surveillance studies. We selected TAC for use in the Aetiology of Neonatal Infection in South Asia (ANISA) study for identifying etiologies of severe disease in neonates in Bangladesh, India, and Pakistan. Here we report optimization of TAC to improve pathogen detection and overcome technical challenges associated with use of this technology in a large-scale surveillance study. Specifically, we increased the number of assay replicates, implemented a more robust RT-qPCR enzyme formulation, and adopted a more efficient method for extraction of total nucleic acid from blood specimens. We also report the development and analytical validation of ten new assays for use in the ANISA study. Based on these data, we revised the study-specific TACs for detection of 22 pathogens in NP/OP swabs and 12 pathogens in blood specimens as well as two control reactions (internal positive control and human nucleic acid control) for each specimen type. The cumulative improvements realized through these optimization studies will benefit ANISA and perhaps other studies utilizing multiple-pathogen detection approaches. These lessons may also contribute to the expansion of TAC technology to the clinical setting.