Rupa Singh

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.

Treatment of visceral leishmaniasis in south-eastern Nepal: decreasing efficacy of sodium stibogluconate and need for a policy to limit further decline

Sodium stibogluconate (SSG) is the first-line therapy for visceral leishmaniasis (VL) in south-eastern Nepal. Recent studies from the neighbouring state of Bihar, India, have shown a dramatic fall in cure rates with treatment failure occurring in up to 65% of VL patients treated with SSG. A prospective study was conducted at a tertiary-level hospital located in south-eastern Nepal from July 1999 to January 2001. Parasitologically proven kala-azar patients with no previous history of treatment for VL were treated with SSG 20 mg/kg/d for 30 d which was extended to 40 d in those with persistent positive parasitology. Of the 110 patients who completed SSG therapy and were assessed at 1 and 6 months, definite cure was achieved in 99 patients (90%) and SSG failure occurred in 11 patients (10%). Except for the presence of hepatomegaly and a lower platelet count there was no clinical or laboratory baseline characteristic associated with treatment failure. A significantly lower cure rate (76%, P = 0.03) was observed in patients from the district of Saptari, which borders the antimony-resistant VL areas of Bihar. The efficacy of SSG as a first-line treatment for VL in south-eastern Nepal was still satisfactory, except for the patients living closer to the antimony-resistant VL areas of India. These findings indicate that the spread of resistance to antimonials is already taking place in Nepal and that a policy to control further spread should be urgently implemented.

Evaluation of a urinary antigen‐based latex agglutination test in the diagnosis of kala‐azar in eastern Nepal

Background  We evaluated the diagnostic accuracy as well as the reproducibility of the urine latex agglutination test ‘KAtex’ in the diagnosis of kala‐azar in patients recruited at a tertiary care centre in Dharan, Nepal, between November 2000 and January 2002.

Prospective evaluation and comparison of the direct agglutination test and an rK39‐antigen‐based dipstick test for the diagnosis of suspected kala‐azar in Nepal

The diagnosis of visceral leishmaniasis (kala‐azar) remains difficult in rural endemic areas and practical and reliable tests are badly needed. Two serological tests, the Direct Agglutination Test (DAT) and an rK39‐antigen‐based dipstick test, were compared to parasitological diagnosis in a group of 184 patients presenting at a tertiary care centre in south‐eastern Nepal with a history of fever ≥14 days and splenomegaly; 139 patients had a parasitologically proven kala‐azar and 45 patients had a negative parasitological work‐up. The rK39 dipstick showed a sensitivity of 97% and a specificity of 71%. The DAT was up to 99% sensitive with a low cut‐off titre (1:400) but its specificity did not exceed 82% even with a high cut‐off titre (1:51 200). Both tests could be used for screening suspect patients in endemic areas. However, their use as confirmatory tests should be restricted to situations where the proportion of kala‐azar among clinical suspect patients is high. The rK39 dipstick is cheaper and easier to use than the DAT and could be used widely provided that both its performance and production remain stable.

Sodium stibogluconate cardiotoxicity and safety of generics

Between April 9 and May 5 2000, an outbreak of fatal cardiotoxicity occurred in Nepal amongst visceral leishmaniasis patients treated with a recently introduced batch of generic sodium stibogluconate (SSG) from GL Pharmaceuticals, Calcutta, India. Eight (36%) of 23 patients treated with this batch died, and in 5 (23%) death was attributed to the cardiotoxicity of the drug. This contrasts with the low total death rate (3.2%) and death rate due to cardiotoxicity (0.8%) observed among 252 patients treated between August 1999 and December 2001 with generic SSG from Albert David Ltd, Calcutta, India. These data show that every batch of generic SSG should be subject to rigorous quality control prior to use.

Clinico-laboratory profile and outcome of Japanese encephalitis in Nepali children

Abstract Background: Japanese encephalitis (JE) is associated with high mortality and neurological sequelae. The unpredictable course and lack of specific treatment pose major challenges in management. The tropical climate and paddy ecosystem in Nepal provide a suitable setting. Aims: To determine the aetiology of febrile encephalopathy and describe the clinico-laboratory profile and outcome of JE in Nepali children. Methods: A hospital-based prospective and observational study was conducted over a 1-year period (2000–2001). Children aged from >1 month to 14 years with fever >38°C for <2 weeks and altered sensorium were recruited. JE was confirmed by anti-JE IgM in cerebrospinal fluid and/or serum. Results: Of 117 consecutively enrolled patients, 58 had JE. Ten patients had concomitant infections, four with malaria and six with bacterial meningitis, and were excluded from analysis. Clinical findings were as follows: boys, 69%; age 4–14 years, 71%; presentation during summer and autumn, 83%; fever >3 days, 69%; altered sensorium <2 days, 50%; Glasgow coma score 8–12, 63%; seizures, 58%. Four (8.3%) died. At discharge, neurological sequelae were detected in 24 (50%) and hemiparesis was the most common form. Longer duration of vomiting, altered sensorium and focal neurological deficit on admission were independently associated with sequelae at discharge. Sequelae persisted in nine (18.8%) at 6 weeks follow-up. Long duration of altered sensorium (β co-efficient 0.35, odds ratio 1.4, p=0.042) and presence of focal neurological deficit on admission (β co-efficient 1.6, odds ratio 5.2, p=0.049) were independent predictors of sequelae at 6 weeks. Conclusion: JE was the commonest cause of febrile encephalopathy. Neurological sequelae were common but resolved in two-thirds of cases.

Study of Japanese encephalitis and other viral encephalitis in Nepali children

Background: A hospital‐based prospective cross‐sectional study was conducted in children aged 1 month–14 years to identify the proportion of viral encephalitis due to Japanese encephalitis (JE) and compare the clinico‐laboratory profile and outcome of JE with that of other viral encephalitis (non‐JE).

Clinical risk factors for therapeutic failure in kala-azar patients treated with pentavalent antimonials in Nepal

Drug-related factors and parasite resistance have been implicated in the failure of pentavalent antimonials (Sb(v)) in the Indian subcontinent; however, little information is available on host-related factors. Parasitologically confirmed kala-azar patients, treatment naïve to Sb(v), were prospectively recruited at a referral hospital in Nepal and were treated under supervision with 30 doses of quality-assured sodium stibogluconate (SSG) 20mg/kg/day and followed for 12 months to assess cure. Analysis of risk factors for treatment failure was assessed in those receiving >or=25 doses and completing 12 months of follow-up. One hundred and ninety-eight cases were treated with SSG and the overall cure rate was 77.3% (153/198). Of the 181 cases who received >or=25 doses, 12-month follow-up data were obtained in 169, comprising 153 patients (90.5%) with definite cure and 16 (9.5%) treatment failures. In the final logistic regression model, increased failure to SSG was significantly associated with fever for >or=12 weeks [odds ratio (OR)=7.4], living in districts bordering the high SSG resistance zone in Bihar (OR=6.1), interruption of treatment (OR=4.3) and ambulatory treatment (OR=10.2). Early diagnosis and supervised treatment is of paramount importance to prevent treatment failures within the control programme.

The functional, social and economic impact of acute encephalitis syndrome in Nepal--a longitudinal follow-up study.

Background Over 133,000 children present to hospitals with Acute Encephalitis Syndrome (AES) annually in Asia. Japanese encephalitis (JE) accounts for approximately one-quarter of cases; in most cases no pathogen is identified and management is supportive. Although JE is known to result in neurological impairment, few studies have examined the wider impact of JE and AES on patients and their families. Methodology/Principal Findings Children (aged 1 month–14 years) with AES were assessed 5–12 months after discharge from two Nepali hospitals. Assessment included clinical examination, the Liverpool Outcome Score (LOS) - a validated assessment of function following encephalitis, questionnaires about the childs social participation since discharge, and out-of-pocket costs to the family. Children were classified as JE or ‘other AES’ based on anti-JE virus antibody titres during acute illness. Contact was made with the families of 76% (73/96) of AES children. Six children had died and one declined participation. 48% (32/66) reported functional impairment at follow-up, most frequently affecting behaviour, language or limb use. Impairment was more frequent in JE compared to ‘other AES’ cases (68% [13/19] versus 40% [19/47]; p = 0.06). 49% (26/53) had improvement in LOS between discharge and follow-up. The median out-of-pocket cost to families, including medical bills, medication and lost earnings was US

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

1151 (10 times their median monthly income) for children with severe/moderate impairment and