Nisha Keshary Bhatta

A Preliminary Randomized Double Blind Placebo-Controlled Trial of Intravenous Immunoglobulin for Japanese Encephalitis in Nepal

Background Japanese encephalitis (JE) virus (JEV) is a mosquito-borne flavivirus found across Asia that is closely related to West Nile virus. There is no known antiviral treatment for any flavivirus. Results from in vitro studies and animal models suggest intravenous immunoglobulin (IVIG) containing virus-specific neutralizing antibody may be effective in improving outcome in viral encephalitis. IVIG’s anti-inflammatory properties may also be beneficial. Methodology/Principal Findings We performed a pilot feasibility randomized double-blind placebo-controlled trial of IVIG containing anti-JEV neutralizing antibody (ImmunoRel, 400mg/kg/day for 5 days) in children with suspected JE at two sites in Nepal; we also examined the effect on serum neutralizing antibody titre and cytokine profiles. 22 children were recruited, 13 of whom had confirmed JE; 11 received IVIG and 11 placebo, with no protocol violations. One child (IVIG group) died during treatment and two (placebo) subsequently following hospital discharge. Overall, there was no difference in outcome between treatment groups at discharge or follow up. Passive transfer of anti-JEV antibody was seen in JEV negative children. JEV positive children treated with IVIG had JEV-specific neutralizing antibody titres approximately 16 times higher than those treated with placebo (p=0.2), which was more than could be explained by passive transfer alone. IL-4 and IL-6 were higher in the IVIG group. Conclusions/Significance A trial of IVIG for JE in Nepal is feasible. IVIG may augment the development of neutralizing antibodies in JEV positive patients. IVIG appears an appealing option for JE treatment that warrants further study. Trial Registration ClinicalTrials.gov NCT01856205

Oral zinc supplementation for reducing mortality in probable neonatal sepsis: a double blind randomized placebo controlled trial.

ObjectiveTo study the role of Zinc in the treatment of neonatal sepsis.DesignDouble blind, randomized, placebo controlled trial.SettingTertiary Care Hospital.Participants614 neonates with probable neonatal sepsis.InterventionThe drug group (n=307) received 1mg/kg/day of elemental zinc, and placebo group (n=307) received the placebo, in addition to antibiotic therapy and supportive care, till the final outcome (discharge/death).Outcome MeasuresDecrease in mortality rates (primary outcome), duration of hospital stay and need of higher lines of antibiotic therapy (secondary outcomes) were tested.ResultsBaseline characteristics of the two groups were similar. No statistically significant differences between drug and placebo group were found in mortality rate (9.77% vs 7.81 %; P=0.393), mean duration of hospital stay (142.85±69.41 hrs, vs. 147.99±73.13 hrs; P=0.841), and requirement of higher lines of antibiotic therapy (13.35% vs 12.05%, P=0.628) after supplementation.ConclusionsThis study does not report decrease in mortality rates, duration of hospital stay and requirement of higher lines of antibiotic therapy following zinc supplementation in neonatal sepsis.

Application of a plain abdominal radiograph transition zone (PARTZ) in Hirschsprung's disease

BackgroundA standard contrast enema for Hirschsprungs disease can sometimes be inconclusive in delineating a transition zone especially in neonates and infants. The aim of this study was to determine the utility and diagnostic accuracy of a plain abdominal radiograph transition zone (PARTZ) in predicting the level of aganglionosis.MethodsA prospective observational study of neonates and infants with biopsy proven Hirschsprungs disease was carried out from March 2004 through March 2006. All patients underwent a plain abdominal radiograph and a contrast enema followed by a rectal biopsy. The transition zone on a plain radiograph (PARTZ) and contrast enema (CETZ) were compared with operative and pathology reports. Results were analyzed by chi square test and expressed as their p values and 95% confidence intervals.ResultsPARTZ and CETZ suggestive of Hirschsprungs disease was seen in 24(89%) and 18(67%) patients respectively. The PARTZ and CETZ matched with the pathologic level of transition zone in 22(92%) and 13(72%) patients, p = 0.001, 95% CI (-1.87 to -0.79). In the 9 (33%) patients in whom contrast enema failed to reveal a transition zone, PARTZ was seen in 6/9(66%) patients and correlated with the pathological level of aganglionosis in 4/6(67%) patients, p = 0.001 95% CI (-1.87 to -0.79). The overall accuracy of PARTZ and CETZ was 96% and 84% respectively, p = 0.008, 95% CI (-6.09 to -3.6).ConclusionA plain abdominal radiographic transition zone is reliable in predicting the level of transition zone in cases of inconclusive contrast enema. It may be particularly helpful developing countries where laparoscopic techniques are not available to accurately identify the transition zone.

Clinical and laboratory study of kala-azar in children in Nepal.

Reports are scanty regarding kala-azar in children in Nepal. In this communication we document 20 children diagnosed to have kala-azar who were admitted and treated at B. P. Koirala Institute of Health Sciences, Dharan, Nepal. The children were between 2 and 14 years old. The duration of illness varied between 12 days and 24 months with a majority (65 per cent) of children being ill for less than 6 months. Hepatomegaly and splenomegaly were seen in 95 and 90 per cent of cases respectively. Splenomegaly was not found in two (10 per cent) children. Anaemia, leucopenia, and thrombocytopenia were seen in 95, 60, and 75 per cent of children respectively. Amastigotes of Leishmania donovani (LD bodies) were demonstrated in Giemsa-stained smears of bone marrow aspirates in 16 (80 per cent) children. All the children responded to treatment with sodium stibogluconate. No mortality was observed. This study emphasizes the importance of kala-azar in children in endemic areas of eastern Nepal.

Urinary screening for detection of renal abnormalities in asymptomatic school children.

Background Urinary screening tests for early detection of renal diseases in asymptomatic school children and adolescents are important in the detection of silent renal diseases. Objectives The purpose of the study was to determine the prevalence of occult renal diseases by dipstick test (reagent strips) in asymptomatic Nepalese children. Patients and Methods A total of 2,243 school children, aged 5–15 years, were screened for urinary abnormalities using dipstick test screening. The children who tested positive in the first screening were re-tested after 2–4 weeks. Results In the first screening, 123 children (5.5%) tested positive for isolated hematuria and proteinuria and for combined hematuria and proteinuria. Of these children, 16 (0.71%) cases tested positive in a second screening. Subsequently, 1 child from the secondary screening group was lost to follow up, 5 tested normal and 10 revealed abnormalities. Glomerulonephritis was the most commonly detected disorder (50%). Conclusions Urinary screening was found to be useful in identifying occult renal diseases in asymptomatic children. Urinary screening would therefore not only help in early detection but also in the prevention of the deterioration of renal function later in life.

Experiences and Lessons from a Multicountry NIDIAG Study on Persistent Digestive Disorders in the Tropics.

Persistent digestive disorders can be defined as any diarrhea (i.e., three or more loose stools per day) lasting for at least two weeks and/or abdominal pain that persists for two weeks or longer [1–3]. These disorders cause considerable morbidity and human suffering, and hence, are reasons why people might seek primary health care. However, in resource-constrained settings of the tropics and subtropics, accurate point-of-care diagnostics are often lacking and treatment is empiric, particularly in remote rural areas with no laboratory infrastructure. As a result, the relative contribution of selected pathogens to the syndrome of persistent digestive disorders is poorly understood, and evidence-based guidelines for patient management in different social-ecological settings are scarce [4–6]. In order to improve the clinical management of patients with disorders caused by neglected tropical diseases (NTDs), the European Commission (EC) funded a five-year study—the Neglected Infectious diseases DIAGnosis (NIDIAG) research consortium. The overarching goal of the NIDIAG consortium is to develop and validate patient-centered diagnosis–treatment guidelines for use at the primary health care level in low- and middle-income countries (http://www.nidiag.org) [3,7–9]. Emphasis is placed on three syndromes: (i) persistent digestive disorders described here; (ii) persistent fever; and (iii) neurological disorders, the latter two of which are detailed in companion pieces published in the same issue of PLOS Neglected Tropical Diseases. With regard to the study on persistent digestive disorders, the main aims are (i) to identify the most important NTDs and other infectious agents that give rise to this clinical syndrome, including their relative frequency; (ii) to assess and compare the accuracy of different diagnostic methods; and (iii) to determine clinical responses to commonly employed empiric treatment options for persistent digestive disorders [9]. To this end, a case–control study has been implemented in four countries: Cote d’Ivoire and Mali in West Africa and Indonesia and Nepal in Asia. An integral part of the NIDIAG consortium is to ensure that good clinical practice (GCP) and good clinical laboratory practice (GCLP) are adhered to while conducting the studies [10,11]. A quality assurance system, which included the development and implementation of a set of standard operating procedures (SOPs), along with on-the-spot staff training and internal and external quality control activities, has been developed at the project level and introduced at each study site. The development of, and adherence to, SOPs within harmonized study protocols were considered crucial steps for maximizing the integrity of laboratory and clinical data across study settings. They also provided the basis on which quality control activities could be performed. For Which Procedures Have SOPs Been Developed? For the study on persistent digestive disorders, 33 specific SOPs have been developed (Supporting Information). As summarized in Table 1, detailed steps on clinical and laboratory procedures, data management, and quality assurance were described. With regard to clinical investigations, SOPs on history taking and clinical examination, assessing inclusion and exclusion criteria, patient recruitment, and study flow were developed (S1-S6). Detailed instructions on how to perform a set of laboratory diagnostic techniques for the detection of helminth and intestinal protozoa infections were included in the laboratory SOPs. Different conventional stool microscopy techniques were combined with more recent rapid antigen detection tests to encompass a broad spectrum of potentially implicated pathogens with high diagnostic accuracy (S7-S20). An overview of the employed diagnostic methods is provided in Table 2. Pertaining to data management, SOPs on completion of case report forms (CRFs) and on various activities (such as data entry, data cleaning, querying, database locking, and backing up data) were also included. To ensure quality control, SOPs on internal quality control activities, external monitoring, and laboratory supervision visits were jointly developed for the three syndromes (S21-S33). Table 1 Set of standard operating procedures (SOPs) used in the NIDIAG study on persistent digestive disorders. Table 2 Laboratory diagnostic techniques used and internally compared in the NIDIAG study on persistent digestive disorders. Of note, all SOPs were developed in English (for use in Nepal) and subsequently translated into French (for use in Cote d’Ivoire and Mali) and Bahasa Indonesia (for use in Indonesia). This comprehensive set of closely interconnected SOPs—which provides guidance on all essential procedures from the first presentation of an individual at a health care center until the final processing of all patient and laboratory data—is displayed in Fig 1. Fig 1 Principal elements of the NIDIAG digestive study and the respective standard operating procedures (SOPs) used. How Was the Development of SOPs Coordinated, and Which Quality Control Measures Were Adopted? The development and harmonization of the various SOPs was coordinated by the quality assurance group of the NIDIAG consortium and the trial management group (TMG) of the digestive syndrome study and followed a standard template and consortium-wide guidelines stipulated in the SOP entitled “SOP on SOP” (S24). This allowed different authors with varied background and writing styles to convey key messages and pass on their expert knowledge in a systematic, standardized manner for the benefit of the end user of all the SOPs. In addition, it provided clear instructions on how the SOPs should be numbered, reviewed, and approved to allow for strict version control. The authors of the SOPs were chosen from within the NIDIAG consortium, and allocation of topics was based on expertise and track record in the clinical, laboratory, data management, and quality assurance components of the study. Experts in the field, at the bench, and at the bedside carefully reviewed and revised the draft SOPs. Before the start of recruitment, local clinical and laboratory teams were trained on the set of SOPs through two hands-on workshops lasting three days each that were conducted on site by relevant experts of the NIDIAG consortium. During these workshops, feedback from the local partners was incorporated to refine the already developed SOPs, and additional SOPs were jointly developed to meet specific demands of local clinical, epidemiologic, and laboratory conditions. For example, in Indonesia, where Kinyoun staining was not available, an SOP pertaining to a slightly modified acid-fast staining technique was developed for the local team instead. Finally, once an SOP was finalized, a member of the TMG would approve it. A quality assurance member of the NIDIAG consortium was tasked to compile and keep updated the final set of SOPs and ensure that the latest versions were available on the NIDIAG intranet for distribution among the different country partners.

Head growth of undernourished children in rural Nepal: association with demographics, health and diet

Background: Brain development in early childhood is a key determinant of later cognition, social achievement and educational success. Head circumference (HC) measurements are a simple method to assess brain growth, yet reports of these measurements are uncommon in nutritional surveys of undernourished children. Objective: To evaluate HC measurements in a population of rural Nepali children and relate these measurements to demographics, health and diet. Methods: An observational study of head growth was nested within a longitudinal evaluation of a livestock-based agricultural intervention in rural Nepal. Between 538 and 689 children (aged 6 months to 8 years) were measured (height, weight, HC) at each of six survey visits. A total of 3652 HC measurements were obtained. Results were converted to Z-scores (WHO Anthro). Results: Mean head circumference Z-scores (HCZ) diminished progressively over the first 4 years of life; a decline of 30% occurred between 3 and 4 years of age (−1.73 to −2.45, P < 0.0001). Overall, 56% of HCZ were <−2. Gender-adjusted HCZ (but not other measurements) were significantly lower for girls than boys [mean (SD) −2.31 (1.0) vs −1.99 (0.094), P < 0.0001]; girls more often had microcephaly (61% vs 50%, P < 0.0001). For children <3 years of age, HCZ were better in those who had eaten two or more animal-source foods (ASFs) within the previous 24 h [−1.69 (.05) vs −2.08 (0.10), P = 0.001] than in those who had eaten none or only one; HCZ correlated with the number of ASFs consumed (P < 0.001). Regression analyses demonstrated that the main determinants of HCZ were age, weight-for-age Z-scores (WAZ) and gender; 43% of the variance in HCZ in younger children was explained by WAZ and ASF consumption. Conclusion: HCs reflect brain size in young children; brain size is linked to cognitive function. Poor head growth represents another facet of the ‘silent emergency’ of child undernutrition. Routine HCZ assessments may contribute to better understanding of the links between poverty and cognitive development.

Clinical and etiological profile of acute febrile encephalopathy in Eastern Nepal

ObjectiveTo investigate the clinical and etiological profile of acute febrile encephalopathy in children presenting to a tertiary care referral center of Eastern Nepal.Methods107 children (aged 1 month to 14 yrs) presenting to the emergency with fever (> 38° C) of less than 2 weeks duration with altered sensorium with/or without seizure were prospectively investigated for etiological cause. The investigations included blood and CSF counts, blood and CSF cultures, peripheral smear and serology for malarial parasite, and serology for Japanese encephalitis (JE) virus. Other investigations included EEG and CT or MRI wherever indicated.ResultsThe most common presenting complaints apart from fever and altered sensorium were headache and vomiting. Convulsions, neck rigidity, hypertonia, brisk deep tendon reflexes, extensor plantar response and focal neurological deficits were seen in 50%, 57%, 22.4%, 28%, 39.3% and 9.3% of the subjects, respectively. The diagnoses based on clinical presentation and laboratory findings were pyogenic meningitis in 45 (42%), non JE viral encephalitis in 26 (25%), JE in 19 (18%), cerebral malaria in 8 (7%), herpes encephalitis and tubercular meningitis in 4 (4%) each, and typhoid encephalopathy in 1 case.ConclusionPyogenic meningitis and viral encephalitis including JE are the most common causes of acute presentation with fever and encephalopathy. Preventive strategies must be directed keeping these causes in mind.

Intrauterine omphalic ileal entrapment as an unusual cause of ileal Atresia: Report of a case

We report a case of ileal atresia (IA) caused by an omphalic ring closure anomaly. A 2-day-old male neonate started vomiting bile, accompanied by abdominal distention. Laparotomy revealed that the distal part of the ileum was entrapped within the omphalic ring and that this entrapped segment of ileum was atretic. To our knowledge, this potential mechanism of IA has not been described before.

Current status of inpatient HIV care at a tertiary care center in Nepal

The success of the WHOs ‘3 by 5’ programme will depend on the ability of developing countries to provide antiretroviral therapy. The purpose of this study was to determine the current status of HIV care at a major teaching hospital in eastern Nepal. A retrospective cohort study was conducted of admitted HIV-infected patients at BPKIHS between 1993 and 2003, evaluating reasons for admission and the care received. There were 2, 2, 2, 3, 5 and 18 admissions, respectively, from 1998 to 2003. Only 4 were female patients. Two were children, both admitted in the last y studied. 10 admissions (31% of the total) were for opportunistic infections (OIs). Seven patients were prescribed OI prophylaxis, with incorrect dosages in 6. Four patients were prescribed antiretroviral therapy, all in inappropriate dosages or combinations. 13 patients were rapidly discharged without further care as soon as a diagnosis of HIV was made. Hospital admissions of HIV-infected individuals are increasing rapidly. Important segments of the HIV-infected population such as women and children are not receiving medical services. Most admissions are not due to OIs. The care of HIV-infected patients even at a major tertiary care teaching hospital in Nepal is sub-optimal.