Mucosal immunity to poliovirus in children 0-15 years of age: A community-based study in Karachi, Pakistan in 2019.

This study assesses poliovirus type 1 (PV1) immunity in children to inform the contribution of mucosal immunity in and preventing poliovirus circulation. A community-based study was conducted in peri-urban Karachi, Pakistan. Randomly selected children (0-15 years) received oral poliovirus vaccine (OPV) challenge dose. Blood and stool samples were collected at several time points and evaluated for polio-neutralizing antibodies and serotype-specific poliovirus, respectively. 81/589 (14%) children excreted PV1 7 days post-OPV-challenge; 70/81 (86%) were seropositive at baseline. 12/610 (2%) were asymptomatic Wild Poliovirus Type 1 (WPV1) excretors. Most poliovirus excretors had humoral immunity, suggesting mucosal immunity in these children likely waned or never developed. Without mucosal immunity, they are susceptible to poliovirus infection, shedding, and transmission. Asymptomatic WPV1 excretion suggests undetected poliovirus circulation within the community.

Two-Year Duration of Immunity of Inactivated Poliovirus Vaccine: A Follow-up Study in Pakistan in 2020.

This was a follow-up study conducted in 2020 assessing changes in levels of type 2 poliovirus-neutralizing antibodies 2 years postimmunization in children who received inactivated poliovirus vaccine (IPV) in Karachi, Pakistan. Unexpectedly, the findings revealed an increase in seroprevalence of type 2 antibodies from 73.1% to 81.6% 1 year and 2 years after IPV, respectively. The increase in type 2 immunity could result from the intensive transmission of circulating vaccine-derived poliovirus type 2 (cVDPV2) in Karachi during the second year of IPV administration. This study suggests that the cVDPV2 outbreak detected in Pakistan infected large proportions of children in Karachi. Clinical Trials Registration . NCT03286803.

Mutational analysis in different genes underlying severe combined immunodeficiency in seven consanguineous Pakistani families.

BACKGROUND: Severe Combined Immunodeficiency (SCID) is an autosomal recessive inborn error of immunity (IEI) characterized by recurrent chest and gastrointestinal (GI) infections and in some cases associated with life-threatening disorders. METHODOLOGY AND RESULTS: This current study aims to unwind the molecular etiology of SCID and also extended the patients' phenotype associated with identified particular variants. Herein, we present 06 disease-causing variants identified in 07 SCID-patients in three different SCID related genes. Whole Exome Sequencing (WES) followed by Sanger Sequencing was employed to explore genetic variations. The results included identification of two previously reported heterozygous variants in homozygous form for the first time in RAG1gene [(p.Arg410Gln);(p.Arg737His)], followed by a recurrent variant (p.Trp959*) in RAG1, a novel variant in IL2RG (p.Asp48Lfs*24), a recurrent variant in IL2RG (p.Gly271Glu) and a recurrent variant in DCLRE1C (p.Arg191*) gene. CONCLUSION: To conclude, the immune-profiling and WES revealed two novel, two as homozygous state for the first time, and two recurrent disease causing variants contributing valuably to our existing knowledge of SCID.

Biomarker-Based Risk Stratification in Pediatric Sepsis From a Low-Middle Income Country.

OBJECTIVES: Most biomarker studies of sepsis originate from high-income countries, whereas mortality risk is higher in low- and middle-income countries. The second version of the Pediatric Sepsis Biomarker Risk Model (PERSEVERE-II) has been validated in multiple North American PICUs for prognosis. Given differences in epidemiology, we assessed the performance of PERSEVERE-II in septic children from Pakistan, a low-middle income country. Due to uncertainty regarding how well PERSEVERE-II would perform, we also assessed the utility of other select biomarkers reflecting endotheliopathy, coagulopathy, and lung injury. DESIGN: Prospective cohort study. SETTING: PICU in Aga Khan University Hospital in Karachi, Pakistan. PATIENTS: Children (< 18 yr old) meeting pediatric modifications of adult Sepsis-3 criteria between November 2020 and February 2022 were eligible. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Plasma was collected within 24 hours of admission and biomarkers quantified. The area under the receiver operating characteristic curve for PERSEVERE-II to discriminate 28-day mortality was determined. Additional biomarkers were compared between survivors and nonsurvivors and between subjects with and without acute respiratory distress syndrome. In 86 subjects (20 nonsurvivors, 23%), PERSEVERE-II discriminated mortality (area under the receiver operating characteristic curve, 0.83; 95% CI, 0.72-0.94) and stratified the cohort into low-, medium-, and high-risk of mortality. Biomarkers reflecting endotheliopathy (angiopoietin 2, intracellular adhesion molecule 1) increased across worsening risk strata. Angiopoietin 2, soluble thrombomodulin, and plasminogen activator inhibitor 1 were higher in nonsurvivors, and soluble receptor for advanced glycation end-products and surfactant protein D were higher in children meeting acute respiratory distress syndrome criteria. CONCLUSIONS: PERSEVERE-II performs well in septic children from Aga Khan University Hospital, representing the first validation of PERSEVERE-II in a low-middle income country. Patients possessed a biomarker profile comparable to that of sepsis from high-income countries, suggesting that biomarker-based enrichment strategies may be effective in this setting.

A descriptive case series of necrotising enterocolitis; occurrence at Aga Khan University Hospital.

The objective of this study was to determine the frequency and outcome of preterm infants diagnosed with Necrotising Enterocolitis (NEC). In a case series, 320 preterm infants were enrolled during a period of 12 months at Aga Khan University Hospital, Karachi, a tertiary care hospital. Diagnosis and staging was done as per Bell's staging criteria. Possible confounders were filtered. Analysis was based on the form of treatment and symptom progression. During the study, NEC was observed in 29(9.06%) babies of which stages I, II and III were 69%, 24% and 7%, respectively. Outcome analysis showed that among the 29 neonates diagnosed with NEC, 23 were discharged and 6 expired. A 9% prevalence observed during the study suggests this to be to be a major challenge in neonatology. Mortality outcome of 21% diagnosed with NEC recommends an early diagnosis coupled with prompt and appropriate treatment and preventive measures to reduce the burden of NEC in future.

Epidemiological, clinical, and radiological comparison of adult and pediatric features in COVID-19: A scoping review.

OBJECTIVE: To assess epidemiological, clinical, and radiological characteristics of the coronavirus disease in children and adults. METHODS: The scoping review comprised search on PubMed and Scopus Cochrane databases from January 2020 to April 2021 for English-language articles dealing with clinical and radiological manifestations amongst children and adults affected by coronavirus disease. Two reviewers independently screened the titles and abstracts. RESULTS: Of the 389 studies initially identified, 39(10%) were reviewed in detail. Data suggested that children were less frequently affected by the coronavirus disease. The affected children showed milder disease with low case fatalities compared to the adults. CONCLUSIONS: There exists significant gaps in knowledge of clinical and radiological aspects of coronavirus disease, but the available scientific data showed that the disease seems to be unusual in children.

One-Year Decline of Poliovirus Antibodies Following Fractional-Dose Inactivated Poliovirus Vaccine.

BACKGROUND: Fractional dose (one-fifth of full intramuscular dose) of inactivated poliovirus vaccine (fIPV) administered intradermally is used as IPV dose-sparing strategy. We compared the rate of decline of poliovirus antibodies (PVA) in recipients of 2 doses of fIPV or IPV. METHODS: A community-based randomized controlled trial was conducted in Karachi, Pakistan. Children aged 14 weeks were randomized into fIPV or full IPV (study arms A, B) and received 1 vaccine dose at age 14 weeks and 1 at age 9 months. PVAs were measured at age 14, 18 weeks and 10, 21 months. RESULTS: Seroprevalence of poliovirus type 2 antibodies in 170/250 (68%) children after 2 IPV or fIPV doses at age 10 months in A and B reached 100% vs 99% (P = .339), and at 21 months, 86% vs 67% (P = .004). Between age 10 and 21 months antibody log2 titers dropped from ≥ 10.5 to 6.8 in A and from 9.2 to 3.7 in B. CONCLUSIONS: There was a significant decline in antibody titers 12 months following the second IPV dose. The slope of decline was similar for full IPV and fIPV recipients. The results provide further evidence that fIPV is a viable option for IPV dose-sparing. CLINICAL TRIALS REGISTRATION: NCT03286803.

Antimicrobial Stewardship - Do we need it in Pakistan?

In order to identify the literature and research available on development and implementation of Antimicrobial Stewardship Programme (ASP) in Pakistan, a systematic search of various electronic databases such as PubMed, Cochrane, CINAHL and PakMedinet from January 1, 2008 till November 2018 was conducted. Studies were included if they were focused around the development and implementation of the ASP within Pakistan. The search revealed that a significant knowledge gap exists regarding antimicrobial/antibiotic stewardship within Pakistan and not much is known about the current status of the development and implementation of antimicrobial stewardship programme. Only two research studies were found to be significant. Antimicrobial Stewardship Programme's development and implementation is highly essential and important. Currently, there exists a huge knowledge and systematic gap regarding ASP implementation at healthcare institutions.

Surgical-site infections in emergency abdominal paediatric surgeries at a tertiary-care hospital in Pakistan.

A retrospective chart review was carried out in children (neonates to 18 years) who underwent acute surgical abdominal exploration during 2012-2016 at the Aga Khan University Hospital, Karachi, to evaluate the postoperative surgical site infection rates in emergency paediatric abdominal surgery. Incidence of surgical site infection (SSI) was estimated. P-value was calculated, chisquare and non-parametric tests were performed by comparing pre-surgical and post-surgical procedure pathogen occurrence and pre-procedure wound status. Pathogen occurrence related to time-trend of 98 paediatric patients who underwent emergency abdominal surgery was plotted. Of the 94 who were discharged in stable condition, it was found that there was no significant difference between pre- and postsurgical pathogens. Escherichia coli (n=10) was found to be the most common pathogen. Contaminated wounds were associated with higher SSI (p=0.036, OR 1.95 95% CI 0.7-5.4). The study found that pre-surgery wound status could be an indicator for risk of SSI in a post-operative scenario.

Paediatric respiratory isolation: A challenge for a secondary care hospital! A service innovation project.

OBJECTIVE: The aim of this project was to broaden the secondary care hospital's scope of services and provide safe, effective and quality care for the patient presenting with measles. METHODS: Six Sigma DMAIC [define measure, analyze, improve, and control (DMAIC)] methodology was used in this quality improvement project. The quality project was started in October 2015 using a Gantt chart quality tool. RESULTS: The paediatric team with the support of administration of the hospital has established isolation rooms and devised a policy for the care and management of patient with airborne infection to avoid cross transmission. During six months period after establishment of isolation room there were sixty two suspected or confirmed measles cases who were admitted in our hospital, out of them only 4(6.4%) of patients were referred because of their sick condition and need of ventilator support. Further, the percentage of patient's satisfaction level also improved from 60 to 80%. CONCLUSIONS: After this clinical service innovation, there was significant reduction in referrals of measles patients to another hospital and consequently there was an increase in the patient's satisfaction.

Impact of maternal education about complementary feeding on their infants' nutritional outcomes in low- and middle-income households: a community-based randomized interventional study in Karachi, Pakistan.

This cluster-randomized interventional trial at periurban settings of Karachi was conducted to evaluate the impact of maternal educational messages regarding appropriate complementary feeding (CF) on the nutritional status of their infants after 30 weeks of educational interventions delivered by trained community health workers. Mothers in the intervention group received three education modules about breastfeeding (BF) and appropriate CF at a baseline visit and two subsequent visits 10 weeks apart. The control group received advice about BF according to national guidelines. Infants' growth [weight, length, and mid-upper arm-circumference (MUAC), stunting, wasting, and underweight] were measured at four time points. At the end of the study, infants in the intervention group had a higher mean weight of 350 g (p=0.001); length of 0.66 cm (p=0.001), and MUAC of 0.46 cm (p=0.002) compared to the controls; proportionate reduction of stunting and underweight were 10% (84% vs. 74%; OR(adj) 8.36 (5.6-12.42) and 5% (25% vs. 20%; OR(adj) 0.75 (0.4-1.79) in the intervention compared to the control group. For relatively food-secure populations, educational interventions about appropriate CF to mothers had a direct positive impact on linear growth of their infants.

The upsurge of SSPE--a reflection of national measles immunization status in Pakistan.

Subacute sclerosing panencephalitis (SSPE) is a rare disorder in the developed world. However, an upsurge has been seen lately in our part of the world owing to inadequate measles immunization coverage. At the midst of our struggle against polio, we are struggling with the war against other vaccine-preventable childhood illnesses like measles. The increasing numbers of SSPE that we reported over the past half decade suggest an underlying periodic measles epidemic in Pakistan. In addition, children are now presenting with SSPE in early childhood, warranting a relook, reinforcement and strengthening of primary immunization and mandatory two-dose measles vaccination for all children nationwide. Previously undertaken Measles Supplementary Immunization Activity were a failure in terms of providing the expected cover against measles in young children. Intensive surveillance and establishment of SSPE registers at the district level is essential for eradication of this easily preventable disorder. Unless timely efforts are made to achieve global immunization, SSPE is bound to add to the national disability burden.

Burden of Respiratory Disease in Pediatric Intensive Care Unit: Experience from a PICU of a Tertiary Care Center in Pakistan.

Introduction: We aimed to determine the burden of respiratory disease by examining clinical profiles and associated predictors of morbidity and mortality of patients admitted to a Pediatric Intensive Care Unit (PICU) in Pakistan, a resource limited country. We also stratified the respiratory diseases as defined by the Pediatric Advanced Life Support (PALS) Classification. Methods: A retrospective study was conducted on children aged 1 month to 18 years who were diagnosed with respiratory illness at the PICU in a tertiary hospital in Karachi, Pakistan. Demographics, essential clinical details including immunization status, and the outcome in terms of mortality or survival were recorded. Predictors of mortality and morbidity including prolonged intubation and mechanical ventilation in the PICU were analyzed using the chi-square test or Fischer's exact test as appropriate. Results: 279 (63.8% male; median age 9 months, IQR 4-36 months) patients were evaluated of which 44.2% were malnourished and 23.3% were incompletely immunized. The median length of stay in the PICU was 3 days (IQR 2-5 days). Pneumonia was the principal diagnosis in 170 patients (62%) and accounted for most deaths. 76/279 (27.2%) were ventilated, and 67/279(24.0%) needed inotropic support. A high Pediatric Risk of Mortality (PRISM) III score, pneumothorax, and lower airway disease were significantly associated with ventilation support. The mortality rate of patients was 14.3%. Predictors of mortality were a high PRISM III score (OR 1.179; 95% CI 1.024-1.358, P=0.022) and a positive blood culture (OR 4.305; 95% CI 1.062-17.448, P=0.041). Conclusion: Pneumonia is a significant contributor of respiratory diseases in the PICU in Pakistan and is the leading cause of morbidity and mortality. A high PRISM III score, pneumothorax, and lower airway disease were predictors for ventilation support. A high PRISM III score and a positive blood culture were predictors of patient mortality in our study.

Prevalence and correlates of paediatric guideline non-adherence for initial empirical care in six low and middle-income settings: a hospital-based cross-sectional study.

OBJECTIVES: This study evaluated the prevalence and correlates of guideline non-adherence for common childhood illnesses in low-resource settings. DESIGN AND SETTING: We used secondary cross-sectional data from eight healthcare facilities in six Asian and African countries. PARTICIPANTS: A total of 2796 children aged 2-23 months hospitalised between November 2016 and January 2019 with pneumonia, diarrhoea or severe malnutrition (SM) and without HIV infection were included in this study. PRIMARY OUTCOME MEASURES: We identified children treated with full, partial or non-adherent initial inpatient care according to site-specific standard-of-care guidelines for pneumonia, diarrhoea and SM within the first 24 hours of admission. Correlates of guideline non-adherence were identified using generalised estimating equations. RESULTS: Fully adherent care was delivered to 32% of children admitted with diarrhoea, 34% of children with pneumonia and 28% of children with SM when a strict definition of adherence was applied. Non-adherence to recommendations was most common for oxygen and antibiotics for pneumonia; fluid, zinc and antibiotics for diarrhoea; and vitamin A and zinc for SM. Non-adherence varied by site. Pneumonia guideline non-adherence was more likely among patients with severe disease (OR 1.82; 95% CI 1.38, 2.34) compared with non-severe disease. Diarrhoea guideline non-adherence was more likely among lower asset quintile groups (OR 1.16; 95% CI 1.01, 1.35), older children (OR 1.10; 95% CI 1.06, 1.13) and children presenting with wasting (OR 6.44; 95% CI 4.33, 9.57) compared with those with higher assets, younger age and not wasted. CONCLUSIONS: Non-adherence to paediatric guidelines was common and associated with older age, disease severity, and comorbidities, and lower household economic status. These findings highlight opportunities to improve guidelines by adding clarity to specific recommendations.

Childhood growth during recovery from acute illness in Africa and South Asia: a secondary analysis of the childhood acute illness and nutrition (CHAIN) prospective cohort.

Background: Growth faltering is well-recognized during acute childhood illness and growth acceleration during convalescence, with or without nutritional therapy, may occur. However, there are limited recent data on growth after hospitalization in low- and middle-income countries. Methods: We evaluated growth following hospitalization among children aged 2-23 months in sub-Saharan Africa and South Asia. Between November 2016 and January 2019, children were recruited at hospital admission and classified as: not-wasted (NW), moderately-wasted (MW), severely-wasted (SW), or having nutritional oedema (NO). We describe earlier (discharge to 45-days) and later (45- to 180-days) changes in length-for-age [LAZ], weight-for-age [WAZ], mid-upper arm circumference [MUACZ], weight-for-length [WLZ] z-scores, and clinical, nutritional, and socioeconomic correlates. Findings: We included 2472 children who survived to 180-days post-discharge: NW, 960 (39%); MW, 572 (23%); SW, 682 (28%); and NO, 258 (10%). During 180-days, LAZ decreased in NW (-0.27 [-0.36, -0.19]) and MW (-0.23 [-0.34, -0.11]). However, all groups increased WAZ (NW, 0.21 [95% CI: 0.11, 0.32]; MW, 0.57 [0.44, 0.71]; SW, 1.0 [0.88, 1.1] and NO, 1.3 [1.1, 1.5]) with greatest gains in the first 45-days. Of children underweight (<-2 WAZ) at discharge, 66% remained underweight at 180-days. Lower WAZ post-discharge was associated with age-inappropriate nutrition, adverse caregiver characteristics, small size at birth, severe or moderate anaemia, and chronic conditions, while lower LAZ was additionally associated with household-level exposures but not with chronic medical conditions. Interpretation: Underweight and poor linear growth mostly persisted after an acute illness. Beyond short-term nutritional supplementation, improving linear growth post-discharge may require broader individual and family support. Funding: Bill & Melinda Gates FoundationOPP1131320; National Institute for Health ResearchNIHR201813.

Situational analysis of antimicrobial stewardship program (ASP) among public and private sector tertiary care hospitals in Karachi, Pakistan: A qualitative case study.

Objective: To assess the current status of implementation of the Antimicrobial Stewardship Program (ASP) across Tertiary Care Hospitals in Karachi, Pakistan. Design: Exploratory qualitative case study. Setting: Public and private tertiary care hospitals in Karachi, Pakistan. Participants and Methods: The study data were collected from 3 public and 4 private tertiary care hospitals. Twenty-eight in-depth interviews were conducted from the Chief Executive Officer, Chief Medical Officer, Medical Superintendent, and departmental heads of internal medicine, general surgery, and pediatric, respectively. Purposive sampling was done to include higher and middle managers, whereas the infectious diseases consultant, infectious diseases/clinical pharmacist, and clinical microbiologist were interviewed through snowball sampling methodology. Analysis was done using NVivo. Data were source-triangulated within and among the study setting and study participants. Results: We found that more than two-thirds (n = 5, 71%) of tertiary care hospitals in Karachi do not have a structured ASP which includes major public sector hospitals (n = 3, 43%) and half of the private sector hospitals (n = 4, 29%). The study results led to four broad themes, (1) ASP structure, (2) ASP interventions, (3) hospital medical record-keeping system, and (4) structured way for analyzing and reporting mechanism of data related to the ASP. At H1 and H2, there was a consistency in ASP structure and interventions, whereas paucity seen among remaining tertiary care hospitals. Conclusion: There is an alarming need for ASP in the public and private sector hospitals in Karachi. This study can inform future stakeholders regarding ASP and strategies for structural change at hospitals.

Complementary Feeding Pattern and Nutritional Status of Children.

OBJECTIVE: To determine the complementary feeding patterns and their association with malnutrition. STUDY DESIGN: Prospective observational study. Place and Duration of the Study: Outpatient clinics of Aga Khan University Hospital, Pakistan, from June to November 2019. METHODOLOGY: A total of 207 children from age six to twenty-four months, who presented in the outdoor clinics of the study place, were enrolled. Data were recorded in a predesigned data sheet adopted from the infant and young child feeding module. Chi-square test was applied post-stratification and a p-value of <0.05 was taken as significant. RESULTS: Among a total of 207 children, 115 (55.6%) were males and 92 (44.4%) were females, with a mean age of 14.15 ± 5.6 months. Complementary feeding was started at an appropriate age in 124 (60%) children. Normal weight was seen in 133 (64.3%) children, while 73 (35.3%) were underweight. Stunting was presented in 44 (21.3%) children, whereas 163 (78.7%) children were of normal length. The most common reason for early initiation of complementary feeding was difficulty in continuing to breastfeed (n=50, 24.2%); the most common reason behind late complementary feeding was bottle feeding (n=45, 21.7%). CONCLUSION: Only sixty percent of mothers living in an urban setting started complementary feeding at an appropriate age. Various myths are counteracting complementary feeding practices. KEY WORDS: Complementary feeding, Infant's nutrition, Stunting, Wasting, Z-score.

Impact of COVID-19 on feto-maternal and neonatal health in Karachi, Pakistan, A retrospective cohort study.

Scientific literature suggests that pregnant women are at greater risk of acquiring a more severe form of COVID-19 exposing both mother and child to a higher risk of obstetric and neonatal complications. These include increased hospitalization rates, ICU admissions, or ventilatory support among pregnant women when compared to COVID-19 negative pregnant womenA case-control study was conducted at the Aga Khan University Hospital, Karachi, Pakistan with the objective of evaluating the clinical presentation of COVID-19 in pregnancy and its effect on maternal and neonatal outcomes. Data was retrospectively collected from April 2020 till January 2022 of obstetric patients with COVID-19 positive cases and were compared with COVID-19 negative cases from the same time. A total of 491 women were included in the study, 244 cases and 247 controls. The most common complication amongst cases was gestational diabetes mellitus (n = 59, 24%), followed by gestational hypertension (n = 16, 31.7%), pre-eclampsia (n = 13, 5%) Pre-rupture of membrane (85.7%). Amongst the COVID positive mothers the most common presenting complaints were fever followed by dry cough, headache, and shortness of breath. It was observed that COVID-19 did not result in increased adverse maternal or neonatal outcomes compared to COVID-19 negative mothers.

Spinal muscular atrophy: clinical spectrum and genetic mutations in Pakistani children.

BACKGROUND: In Pakistan the rate of consanguineous marriages is high, thus, the chance of incidence of autosomal recessive disorders is likely to be high. The aim of this study is to investigate the clinical characteristics and genetics of spinal muscular atrophy (SMA) in children who presented to Aga Khan University, Karachi. MATERIALS AND METHODS: This study was a retrospective review of the medical charts of children (neonate: 15 years) with discharge diagnosis of SMA during last 10 years. Demographic features, consanguinity, and diagnostic analysis (including genetic analysis) were noted. RESULTS: During the study period 67 children had a discharge diagnosis of SMA. Werdnig Hoffman disease (SMA type I) was the commonest variant seen in 37 (56%) children. Overall 68% were infants. High parental consanguinity was observed in 68% of the study cohort. The history of delayed development and undiagnosed early death was observed in the families of 19 children. Genetic testing was performed in 22 (33%) children. Survival motor neuron (SMN) 1 gene deletion was found in 19 (86%) of the 22 patients in whom the gene analysis was done and 13 (68%) were also positive for neuronal apoptosis inhibitory proteins (NAIP) deletion. CONCLUSION: SMA is not an uncommon neurodegenerative disorder in Pakistan and SMA type I was the most common type. SMN1 gene deletion was the most common genetic deletion found in this study. In addition, family history of developmental delay and frequent early deaths highlights the need for implementation of prenatal diagnosis for early detection, effective control, and management of this disorder in Pakistan.