Thursday, July 19, 2007

Japanese Encephalitis


Introduction
Japanese encephalitis ( previously known as Japanese B encephalitis to distinguish it from von Economo's A encephalitis) is a disease caused by the
mosquito-borne Japanese encephalitis virus. The Japanese encephalitis virus is a virus from the family Flaviviridae. Domestic pigs and wild birds are reservoirs of the virus; transmission to humans may cause severe symptoms. One of the most important vectors of this disease is the mosquito Culex tritaeniorhynchus. This disease is most prevalent in Southeast Asia and the Far East.
Epidemiology
Japanese encephalitis is the leading cause of viral encephalitis in
Asia, with 30,000–50,000 cases reported annually. Case-fatality rates range from 0.3% to 60% and depends on the population and on age. Rare outbreaks in U.S. territories in Western Pacific have occurred. Residents of rural areas in endemic locations are at highest risk; Japanese encephalitis does not usually occur in urban areas. Countries which have had major epidemics in the past, but which have controlled the disease primarily by vaccination, include China, Korea, Japan, Taiwan and Thailand. Other countries that still have periodic epidemics include Vietnam, Cambodia, Myanmar, India, Nepal, and Malaysia.
Clinical features
Japanese encephalitis has an incubation period of 5 to 15 days and the vast majority of infections are asymptomatic: only 1 in 250 infections develop into encephalitis.
Severe rigors mark the onset of this disease in humans. Fever, headache and malaise are other non-specific symptoms of this disease which may last for a period of between 1 and 6 days. Signs which develop during the acute encephalitic stage include neck rigidity,
cachexia, hemiparesis, convulsions and a raised body temperature between 38 and 41 degrees Celsius. Mental retardation developed from this disease usually leads to coma. Mortality of this disease varies but is generally much higher in children. Transplacental spread has been noted. Life-long neurological defects such as deafness, emotional lability and hemiparesis may occur in those who have had central nervous system involvement. In known cases some effects also include, nausea, headache, fever,vomiting and sometimes swelling of the testicles.
Virology
The causative agent Japanese encephalitis virus is an enveloped virus of the genus flavivirus; it is closely related to the
West Nile virus and St. Louis encephalitis virus. Positive sense single stranded RNA genome is packaged in the capsid, formed by the capsid protein. The outer envelope is formed by envelope (E) protein and is the protective antigen. It aids in entry of the virus to the inside of the cell. The genome also encodes several nonstructural proteins also (NS1,NS2a,NS2b,NS3,N4a,NS4b,NS5). NS1 is produced as secretory form also. NS3 is a putative helicase, and NS5 is the viral polymerase. It has been noted that the Japanese encephalitis virus (JEV) infects the lumen of the endoplasmic reticulum (ER) and rapidly accumulates substantial amounts of viral proteins for the JEV.
Japanese Encephalitis is diagnosed by detection of antibodies in serum and CSF (cerebrospinal fluid) by IgM capture
ELISA
Prevention
Infection with JEV confers life-long immunity. All current vaccines are based on the genotype III virus. A formalin-inactivated mouse-brain derived vaccine was first produced in Japan in the 1930s and was validated for use in Taiwan in the 1960s and in Thailand in the 1980s. The widespread use of vaccine and urbanisation has led to control of the disease in Japan, Korea, Taiwan and Singapore. The high cost of the vaccine, which is grown in live mice, means that poorer countries have not been able to afford to give it as part of a routine immunisation programme.
In the UK, the two vaccines used (but which are unlicensed) are JE-Vax® and Green Cross. Three doses are given at 0, 7–14 and 28–30 days. The dose is 1ml for children and adult, and 0.5ml for infants under 36 months of age.
Treatment
There is no specific treatment for Japanese encephalitis and treatment is supportive. There is no transmission from person to person and therefore patients do not need to be isolated.

Management of visceral leishmaniasis : Indian perspective

Introduction
Leishmaniasis encompasses a group of diseases, caused by the obligate intracellular parasite of the genus Leishmania . The disease is transmitted by sandfly, which inoculates the flagellated promastigotes into the skin of the host. In humans, these promastigotes are taken up by macrophages or dendrite cells and transformed into flagellar amastigotes. The future course of infection depends upon the strain of Leishmania and the immune response mounted by the host. Visceral leishmaniasis (VL, kala-azar) is the systemic and disseminated form of the disease, where the primary target of infection is the bone marrow, the spleen and the liver. It is typically caused by L. donovani complex, which includes three species, L. donovani (Indian subcontinent and East Africa), L. infantum (Mediterranean basin) and L. chagasi (Latin America). VL, the most severe form of Leishmaniasis, is characterized by prolonged irregular fever, splenomegaly, hepatomegaly, progressive anemia and pancytopenia along with hypergamm-aglobulinemia. It is uniformly fatal unless treated. Although VL is endemic in 62 countries, 90% of the estimated 500,000 new cases, which occur annually, are confined to the rural areas of India, Nepal, Bangladesh, Sudan and Brazil; as many as one-half of these cases occur in India. There are 30-100 subclinical infections for every overt case of VL. Malnutrition, immunosuppressive drugs or immunocompromised state (HIV infection) can convert these subclinical cases into clinical disease. HIV- Leishmania co-infection is being regarded as an emerging disease, especially in Southern Europe where 25-70% of adults with VL have AIDS as well. VL is now being considered as an important opportunistic infection, among AIDS cases in the Mediterranean basin. With the spreading global pandemic of HIV infection, the HIV-VL co-infection continues to rise, notably in India and Brazil. In these countries, it threatens to urbanize the VL infection, which is essentially a disease of rural areas.
VL in different parts of the world shows considerable epidemiological variation and the clinical presentation also varies considerably; consequently the control measures, case finding and treatment modalities differ in different geographical areas. The scope of the present article is essentially a review of the management of Indian VL, which will be discussed under two heads: (i) diagnosis of VL and (ii) treatment of VL.
Diagnosis of visceral leishmaniasis
VL in India affects more than 100,000 persons every year. The problem is likely to get aggravated by the emerging epidemic of HIV infection. Diagnosis and treatment of this disease is far from satisfactory. Splenic aspirate, although risky, remains the gold standard for the diagnoses of VL. Polymerase chain reaction, using primers to amplify Leishmania kDNA, may emerge as an important tool for the diagnosis of this condition. Out of the battery of serological tests available, k39-based immunochromatographic strip test has become an important and cost effective tool for diagnosis of VL in field conditions, notwithstanding the inherent limitation of antibody-based tests.For treatment of VL, both SbV and Amp B are potentially toxic, and have to be administered parentally for prolonged periods ( > 30 days). A steady decline in the efficacy of SbV in endemic areas of Bihar has rendered this drug useless in this region. Lipid formulations of Amp B are a major advance in the treatment of VL; however, their prohibitive cost puts them beyond the reach of most patients. There is an urgent need to develop this technology indigenously, so that the drug can be reasonably priced to be within reach of poor patients. Miltefosine is the first oral antileishmanial drug, which has proved highly effective in Indian VL. However, there is a potential for development of resistance to this drug by parasite, unless it is judiciously used. Paromomycin, another parental antileishmanial drug, is undergoing phase-III multicenter trials in India.In view of the emergence of parasite resistant to antileishmanial drugs, and limited number of effective antileishmanial drugs, there is an urgent need to revise the strategy of treatment. Combination therapy with multiple drugs is a viable option, which needs to be given serious consideration.
In view of the emergence of parasite resistant to antileishmanial drugs, and limited number of effective antileishmanial drugs, there is an urgent need to revise the strategy of treatment. Combination therapy with multiple drugs is a viable option, which needs to be given serious consideration.
The treatment options for VL are limited and far from satisfactory. Pentavalent antimonials (sodium stibogluconate; SbV) and Amp B have been the two drugs with proven efficacy for treatment of VL. Both the drugs are given parenteraly and are potentially toxic. Paromomycin, an aminoglycoside antibiotic, is currently undergoing Phase-III clinical trail. Recently, for the first time an oral antileishmanial drug "Miltefosine" has proved effective in treating Indian VL and has been registered for treatment of VL.For more than six decades, SbV has been the cornerstone of the treatment of leishmaniasis including VL, in most parts of the world, and 98-99% of patients of VL respond well to the drug. Generic sodium stibogluconate from Indian manufacturers (Albert David Ltd., Kolkata, India) is cheaper than the branded product (Pentostam; GSK), and has been reported to be equally effective and safe in controlled studies from different parts of the world. For treatment of Indian VL, it is used as daily intravenous (IV) or intramuscular (IM) injections in a dose of 20 mg/kg body weight for 30 days. However, the hyperendemic areas of VL in North Bihar have the unique distinction of being the only region in the world from where widespread primary failure of SbV has been reported.Like elsewhere in the world, in India as well, SbV has been used to treat VL for several decades. Till the late 1970s, a small daily dose (10 mg/kg; 600 mg maximum) for 6-10 days was considered adequate for treatment. Increasing refractoriness to SbV led to periodic escalation of the dose of 20 mg/kg/day for 30-40 days, which was reached in the late 1980s. Any increase in the dose beyond this would seriously compromise the safety of the patient. However, with this dosage schedule also, primary unresponsiveness was 52%, whereas 8% patients relapsed. Incidentally, the drug is still responsive in the neighboring state of Uttar Pradesh, where only 2% patients failed treatment. Thus, SbV still remains the treatment of choice for VL in regions like West Bengal or Eastern Uttar Pradesh, and Jharkhand. The resistance is on account of relapse after suboptimal treatment with SbV, which leads to selection of resistant mutants, and these are recycled in anthroponotic foci with a high rate of transmission. Due to this fact, other antileishmanial drugs are likely to meet a similar fate and there is urgent need to protect these drugs before we lose them. The problem is likely to worsen with the increasing incidence of HIV/VL co-infection, as the response to treatment is not as good in these patients and relapse is a rule. These relapsing patients may provide a human reservoir for resistant Leishmania .Pentamidine isothionate was the first drug to be used in SbV refractory patients. However, the declining efficacy of the drug, coupled with serious adverse effects like hypoglycemia, shock, occasional death and above all insulin-dependent diabetes mellitus in a significant proportion of patients, lead to almost abandonment of the drug. For SbV refractory patients, Amp B is currently the alternative treatment of choice. It is a polyene antibiotic used as an antifungal drug, but it also has excellent antileishmanial activity. In SbV refractory regions in India, it has been used extensively with excellent results. Amp B is used in doses of 0.75-1 mg/kg in 5% dextrose infusion up to a total of 15-20 infusions either daily or on alternate days with efficacy of nearly 100%, and resistance has not been reported. It has been recommended as a first line drug by the Indian National Expert Committee for SbV refractory regions. In a recent multicenter study, when Amph B was used as a comparative drug on 99 patients in the dose of 1 mg/kg IV every other day for a total of 15 injections, a final cure rate of 97% was achieved at 6 months follow up. Its drawbacks include high cost, requirement for hospitalization for 5-6 weeks, limited and erratic availability and the need for close monitoring. It is also a toxic drug and its adverse reactions include - universal occurrence of infusion-related fever, chills, vomiting and diarrhea, high incidence of thrombophlebitis and serious and occasionally fatal hypokalemia, renal impairment and cardiac toxicity.To improve the safety of conventional Amp B, lipid formulations have been developed in which deoxycholate has been replaced with other lipids. Clinical application of lipid formulations of Amp B has been one of the most remarkable developments for chemotherapy of VL. The lipid Amp B is taken up by the macrophages and very little free drug is available, minimizing the organ toxicity. These formulations have the advantages that a large daily dose can be given permitting the total dose to be delivered over a short period, minimizing the hospital stay and cost and several fold increase in the capacity of the hospitals to treat larger number of patients. AmBisome (Liposomal Amp B; Gilead Sciences, Foster City, CA, USA) is the only liposomal drug approved by the US FDA for treatment of VL. Several studies are available using this compound for the treatment of Indian VL. In a multicenter trial, a total dose of 3.75 mg, delivered over 5 days in equally divided doses, cured 89% patients with SbV refractory VL. In the same study, a total dose of 15 mg/kg cured 97% patients. However, in a dose of 5 mg/kg administered as single total dose or over 5 days cured 91 and 93% patients, respectively. In another large multicenter study with liposomal amp B in which 203 patients were enrolled at four treatment centers, a total dose of 7.5 mg/kg given as a single dose cured 90% patients. Adverse events were minor and were seen in a small proportion of patients. This kind of treatment is a real breakthrough in the treatment of VL as patients can be treated in a day care setting with a minimum of monitoring. Most importantly, single-dose treatment increases the scarce hospital bed capacity to more than 30 folds. Unfortunately, due to the extremely prohibitive cost of the drug, it remains beyond the reach of most patients. Another Lipid-associated Amp B, Amp B lipid complex (Abelcet; ABLC, Enzon Inc., Piscataway, NJ, USA), has excellent efficacy in Indian VL. In a series of studies, it was established that ABLC in a dose of 10-15 mg/kg delivered over 5-10 days cures 90-100% patients including those with refractory VL While experience with amphocil (Amphotec) (Amp B cholesteryl sulfate complex; InterMune Inc., Brisbane, CA, USA) has been limited, in a study we used it in doses of 7.5, 10 and 15 mg delivered over 6 days, and a cure rate of > 96% was achieved in all the three groups (S. Sundar, unpublished), infusion-related adverse reactions were common.In a recently conducted head to head comparison, we looked at the efficacy and tolerability of conventional Amp B (1 mg/kg on alternate days for 30 days), liposomal Amp B (2 mg/kg/day for 5 days) and ABLC (2 mg/kg/day for 5 days), in treatment of VL patients. The final cure was similar in all the groups, but infusion reactions were universal in Amp B group; lesser with ABLC and least with liposomal Amp B. A liposomal Amp B preparation has been developed in India and is safe and effective in VL. The regimen of 2 mg/kg daily for 10 days cured 100% patients; 3 mg/kg daily for 5 days was efficacious in 90.9%, and 3 mg/kg daily for 7 days in 100% of the unresponsive cases of visceral leishmaniasis. This drug is now commercially available as Fungisome, and needs to be sonicated before administration. Its major advantages are reduced toxicity, shorter duration of treatment, efficacy in resistant cases and reduced cost.Paromomycin (aminosidine), an aminoglycoside, has excellent antileishmanial activity. It has been used either alone or in combination with SbV. In several studies in Africa and India, its efficacy in the treatment of VL has been demonstrated. In a phase-II multicenter randomized controlled trial of aminosidine (paromomycin) for treating VL in north Bihar, Paromomycin was used in daily doses of 12, 16 or 20 mg/kg intramuscularly for 21 days. A cure rate of more than 90% was achieved at 180 days follow-up. A pivotal phase-III multicenter trial on the safety and efficacy of Paromomycin in four different centers of Bihar is nearing completion after which this drug is likely to be registered in several countries including India. The drug is now being manufactured in India and the treatment cost is likely to be between US$10-20 for the whole treatment course for an adult patient.Miltefosine (Impavidoβ) is an alkyl phospholipid developed as an anti-tumor agent, and has excellent antileishmanial activity. It is the first orally effective antileishmanial drug, which is uniformly effective in both naοve as well as SbV refractory patients.In all clinical studies, it cured ³94% patients. It is safe and effective in daily doses of 100-150 mg administered for a duration of 28 days. Its adverse events include mild-moderate vomiting in ~40% patients, and diarrhea in ~20%. In a significant proportion of patients, there is asymptomatic transient elevation of hepatic transaminases. Rarely, it can cause skin allergy and renal insufficiency. In several pediatric studies, it cured 94% of children if a daily dose of 2.5 mg was used for 28 days. Tolerance was good with mild gastrointestinal adverse events like vomiting and diarrhea occurring in 26% children. It was approved in India in 2002 for the treatment of VL at a daily dose of 50 mg in patients weighing <25> 25 kg for 4 weeks. The drug has a long terminal half-life (~7 years). The fact that Miltefosine is administered orally and produces early symptomatic improvement predisposes it for incomplete treatment unless the treatment is strictly supervised. All these factors could encourage development of resistance to the drug and premature end of this very important arsenal against Leishmania unless it is handled and used judiciously.Sitamaquine is an orally administrable primaquine derivative, and though on the horizon for several decades, is still in the early stages of development. Several studies in Kenya, Brazil and India have been done, but in a few patients nephrotoxicity has been observed. Thus, more studies are needed to clearly delineate its safety profile before this drug can reach clinics.HIV/VL co-infectionIn patients with HIV infection, VL is considered to be an AIDS-defining illness, and though predominantly a disease of Mediterranean region and African countries like Ethiopia, its incidence in India is increasing. The treatment of choice is Amp B or its liposomal formulation. Unfortunately, relapse is a rule in co-infection. Reconstitution of immunity by highly active antiretroviral therapy (HAART) has led to a decline in the incidence of VL co-infection in Spain significantly.
(source : Agrawal S, Rai M, Sundar S. Management of visceral leishmaniasis: Indian perspective. J Postgrad Med [serial online] 2005 [cited 2007 Jul 19];51:53-57. Available from: http://www.jpgmonline.com/text.asp?2005/51/5/53/19816)