Prahlad Karki

Increasing Failure of Miltefosine in the Treatment of Kala-azar in Nepal and the Potential Role of Parasite Drug Resistance, Reinfection, or Noncompliance

BACKGROUND Miltefosine (MIL), the only oral drug for visceral leishmaniasis (VL), is currently the first-line therapy in the VL elimination program of the Indian subcontinent. Given the paucity of anti-VL drugs and the looming threat of resistance, there is an obvious need for close monitoring of clinical efficacy of MIL. METHODS In a cohort study of 120 VL patients treated with MIL in Nepal, we monitored the clinical outcomes up to 12 months after completion of therapy and explored the potential role of drug compliance, parasite drug resistance, and reinfection. RESULTS The initial cure rate was 95.8% (95% confidence interval [CI], 92.2-99.4) and the relapse rate at 6 and 12 months was 10.8% (95% CI, 5.2-16.4) and 20.0% (95% CI, 12.8-27.2) , respectively. No significant clinical risk factors of relapse apart from age <12 years were found. Parasite fingerprints of pretreatment and relapse bone marrow isolates within 8 patients were similar, suggesting that clinical relapses were not due to reinfection with a new strain. The mean promastigote MIL susceptibility (50% inhibitory concentration) of isolates from definite cures was similar to that of relapses. Although more tolerant strains were observed, parasite resistance, as currently measured, is thus not likely involved in MIL treatment failure. Moreover, MIL blood levels at the end of treatment were similar in cured and relapsed patients. CONCLUSIONS Relapse in one-fifth of the MIL-treated patients observed in our study is an alarming signal for the VL elimination campaign, urging for further review and cohort monitoring.

A clinico-epidemiological study of snake bite in Nepal.

Envenoming from snake bite is an important medical condition, frequently encountered at the emergency department of BPKIHS hospital (Dharan, Nepal). This is a retrospective study of 52 cases of suspected snake bite who presented at the department from August 1993 to November 1994. Analysis of the data showed that snake bite was more frequent between the ages of 11 to 20 years (36.7%) and 2.5 times more common in males. Fifty-seven per cent of the bites occurred between 1600 h and midnight with highest incidence (51%) occurring during the monsoon (August–October). Twenty per cent of the patients were able to identify the snake species as venomous and 90% of them presented to the hospital within 3 h of being bitten. Sixty per cent of the bites were in the lower limb. Neurotoxicity due to envenoming was recorded in nine patients (17%). No case of coagulopathy was recorded. The overall case fatality was 3.8% but mortality amongst those exhibiting signs of neurotoxicity was 22%.

The alcohol use disorders identification test (AUDIT): validation of a Nepali version for the detection of alcohol use disorders and hazardous drinking in medical settings

BackgroundAlcohol problems are a major health issue in Nepal and remain under diagnosed. Increase in consumption are due to many factors, including advertising, pricing and availability, but accurate information is lacking on the prevalence of current alcohol use disorders. The AUDIT (Alcohol Use Disorder Identification Test) questionnaire developed by WHO identifies individuals along the full spectrum of alcohol misuse and hence provides an opportunity for early intervention in non-specialty settings. This study aims to validate a Nepali version of AUDIT among patients attending a university hospital and assess the prevalence of alcohol use disorders along the full spectrum of alcohol misuse.MethodsThis cross-sectional study was conducted in patients attending the medicine out-patient department of a university hospital. DSM-IV diagnostic categories (alcohol abuse and alcohol dependence) were used as the gold standard to calculate the diagnostic parameters of the AUDIT. Hazardous drinking was defined as self reported consumption of ≥21 standard drink units per week for males and ≥14 standard drink units per week for females.ResultsA total of 1068 individuals successfully completed the study. According to DSM-IV, drinkers were classified as follows: No alcohol problem (n=562; 59.5%), alcohol abusers (n= 78; 8.3%) and alcohol dependent (n=304; 32.2%). The prevalence of hazardous drinker was 67.1%. The Nepali version of AUDIT is a reliable and valid screening tool to identify individuals with alcohol use disorders in the Nepalese population. AUDIT showed a good capacity to discriminate dependent patients (with AUDIT ≥11 for both the gender) and hazardous drinkers (with AUDIT ≥5 for males and ≥4 for females). For alcohol dependence/abuse the cut off values was ≥9 for both males and females.ConclusionThe AUDIT questionnaire is a good screening instrument for detecting alcohol use disorders in patients attending a university hospital. This study also reveals a very high prevalence of alcohol use disorders in Nepal.

Population preference of net texture prior to bed net trial in Kala-Azar-endemic areas.

Prior to a community-based efficacy trial of long-lasting insecticidal nets (LLINs) in the prevention of visceral leishmaniasis (VL; also called kala-azar), a pilot study on preference of tools was held in endemic areas of India and Nepal in September 2005. LLINs made of polyester and polyethylene were distributed to 60 participants, who used the nets sequentially for 7 d. Acceptability and preference were evaluated via indirect indicators through questionnaires at three defined time points before and after use of the LLINs and through focus group discussions (FGDs). In the latter, preferences for color and size were also assessed. Untreated bed nets were owned by 87% of the households prior to the study. All users liked textures of both LLIN types after 7 d of use, but had a slight preference for those made of polyester if they were to recommend a LLIN to relatives or friends (p<0.05), mainly because of their relatively greater softness in comparison to polyethylene LLINs. Users reported that both net types reduced mosquito bites and number of insects, including sand fly (bhusana; genus Phlebotomus), inside the house. Side effects were minor and disappeared quickly. The large-scale intervention trial considered the preferences of the study population to decide on the best tool of intervention—light-blue, rectangular, polyester LLINs of different sizes.

Epidemiological study of kala-azar by direct agglutination test in two rural communities of eastern Nepal.

We conducted a sero‐epidemiological study of kala‐azar in two endemic communities (Kasaini and Gidhaniya) situated in the Terai (plain) of eastern Nepal. Direct agglutination test (DAT) was used as a serological test for screening. Capillary blood samples were collected by filter paper method from 601 (96%) people of a total population of 628 in Kasaini and from 482 (94%) people of 515 in Gidhaniya. Positive DAT titres (1:2000) were found in 66 (6.09%) of 1083 sera tested. The male–female sero‐prevalence ratio was 1.44:1 and the age group of 15 years and above was most affected. Among the bone marrow aspirates collected from 66 DAT seropositive cases, only 19 were positive for Leishmania donovani (LD bodies). Of the 47 DAT seropositive but LD bodies’ negative cases, three were clinically active cases of kala‐azar. Another nine developed clinical symptoms of kala‐azar during 6 months follow‐up and 23 were cases that had received prior treatment for kala‐azar (within 1 year). The results of this study show the potential of the DAT on filter paper as a screening test for the surveillance of kala‐azar at a community level.

Managing a wooden foreign body in the neck

An interesting case is presented of a wooden foreign body in the neck entering through the right lower vestibule of the mouth. The foreign body traveled subcutaneously in the neck and got stuck in the clavicle, without damaging any vital structures. In this case, the authors highlight the mode of entry of the foreign body, the peculiarity of the wooden foreign body, the management protocol and the outcomes of the penetrating neck injury by the wooden stick.

A clinico-epidemiological study of organophosphorus poisoning at a rural-based teaching hospital in eastern Nepal

Thirty-seven patients with severe organophosphorus poisoning (OPP) presented to the emergency ward of BP Koirala Institute of Health Sciences between January 1995 and December 1996. The mean age of patients was 26.9 years. There were 17 (46%) males and 20 (54%) females, with male: female ratio being 1:1.2. Twenty-three (62%) patients were unmarried with 16 (46%) of them students. The most common reason for poisoning was suicide − 32 patients (86.5%). The most commonly involved compound was Metacid (methyl-parathion) − 23 (62%) patients. Ninety per cent of the patients presented within 2 h of ingestion. All patients were managed with intravenous atropine. Pralidoxime was given to patients with nicotinic symptoms and mechanical ventilation initiated in patients with respiratory distress. The mean dose of atropine used in the first 24 h and during the hospital stay was 30.6 mg and 136.7 mg, respectively. The mean duration of treatment was 5.5 days (range 2–20 days). Two patients developed intermediate syndrome and the overall mortality among hospitalized patients was 8%.

Rheumatic heart disease revisited: patterns of valvular involvement from a consecutive cohort in eastern Nepal.

Background The burden of rheumatic heart disease (RHD) continues to be a major contributor to morbidity and premature death in poor and developing countries. We investigated patterns of valvular involvement in patients with RHD as observed in a large tertiary care hospital in eastern Nepal. Methods We retrospectively reviewed transthoracic echocardiography reports from patients diagnosed with RHD between June 1999 and February 2011. Results Among 10 860 transthoracic echocardiography studies, 1055 female and 658 male patients were diagnosed with RHD, 25.7% of the patients being below 20 years of age. Mitral regurgitation was the most common valvular lesion across all age groups irrespective of sex (n = 1321, 77.1%). Female patients were significantly older as compared to male patients at the time of presentation (32.8 ± 15.2 versus 28.5 ± 15.4 years; P < 0.001) and more commonly presented with mitral stenosis as compared to male patients (62.8 versus 51.5%; P < 0.001), with a peak between the age of 30 and 49 years. Conversely, aortic regurgitation was more common in men as compared to women (55.6 versus 48.9%; P = 0.007). Involvement of both the mitral and the aortic valve was observed in 49.8% of the patients and was more common in men as compared to women (52.7 versus 47.8%; P = 0.047). Conclusion In this consecutive cohort of patients with RHD in Nepal differential patterns of valvular involvement are observed across sex and age categories.

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.

Prevalence of Subclinical Rheumatic Heart Disease in Eastern Nepal

IMPORTANCE Although rheumatic heart disease has been nearly eradicated in high-income countries, 3 in 4 children grow up in parts of the world where it is still endemic. OBJECTIVES To determine the prevalence of clinically silent and manifest rheumatic heart disease as a function of age, sex, and socioeconomic status and to estimate age-specific incidence. DESIGN, SETTING, AND PARTICIPANTS In this school-based cross-sectional study with cluster sampling, 26 schools in the Sunsari district in Eastern Nepal with 5467 eligible children 5 to 15 years of age were randomly selected from 595 registered schools. After exclusion of 289 children, 5178 children were enrolled in the present study from December 12, 2012, through September 12, 2014. Data analysis was performed from October 1, 2014, to April 15, 2015. EXPOSURES Demographic and socioeconomic characteristics were acquired in a standardized interview by means of a questionnaire customized to the age of the children. A focused medical history was followed by a brief physical examination. Cardiac auscultation and transthoracic echocardiography were performed by 2 independent physicians. MAIN OUTCOMES AND MEASURES Rheumatic heart disease according to the World Heart Federation criteria. RESULTS The median age of the 5178 children enrolled in the study was 10 years (interquartile range, 8-13 years), and 2503 (48.3%) were female. The prevalence of borderline or definite rheumatic heart disease was 10.2 (95% CI, 7.5-13.0) per 1000 children and increased with advancing age from 5.5 (95% CI, 3.5-7.5) per 1000 children 5 years of age to 16.0 (95% CI, 14.9-17.0) in children 15 years of age, whereas the mean incidence remained stable at 1.1 per 1000 children per year. Children with rheumatic heart disease were older than children without rheumatic heart disease (median age [interquartile range], 11 [9-14] years vs 10 [8-13] years; P = .03), more commonly female (34 [64.2%] vs 2469 [48.2%]; P = .02), and more frequently went to governmental schools (40 [75.5%] vs 2792 [54.5%]; P = .002). Silent disease (n = 44) was 5 times more common than manifest disease (n = 9). CONCLUSIONS AND RELEVANCE Rheumatic heart disease affects 1 in 100 schoolchildren in Eastern Nepal, is primarily clinically silent, and may be more common among girls. The overall prevalence and the ratio of manifest to subclinical disease increase with advancing age, whereas the incidence remains stable at 1.1 per 1000 children per year. Early detection of silent disease may help prevent progression to severe valvular damage.