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Lymphatic Filariasis: Diagnosis and Chemotherapy ApproachesBY: Dr. Saurabha Srivastava | Category: Healthcare | Submitted: 2015-01-12 06:16:13
Article Summary: "The most intriguing and common sub-clinical condition of Lymphatic ﬁlariasis is the asymptomatic microﬁlaraemic individuals. It remains a major concern for the immuno parasitologists due to lack of signs of the disease. In such incertitude and to successfully eliminate LF by the year 2020, there is an urgent need t.."
Lymphatic filariasis (LF), commonly known as elephantiasis is one of the leading causes of permanent, long term disability which affects the social and economic aspects in Asia, Africa and western pacific part of the America (Ottesen 1997; WHO 1995). Globally, this disease is known to affect about 120 million people in endemic countries. In India it has been estimated recently that, there are more than 27 million microfilaraemic carriers, around 20.8 million cases of symptomatic filariasis and about 429 million individuals at risk of filarial infection (Sabesan, 2000). The World Health Assembly has inaugurated the "Global Program to Eliminate Lymphatic Filariasis" (GPELF) and India is one of its signatories (WHO, 2006).
Classification of lymphatic filariasis:
It has been reported that the three major groups of people are found in a filarialendemic area which are associated with specific symptoms and immune responses (Ottesen, 1992; Ottesen, 1994; Evans et al., 1993).
1) Asymptomatic microfilaraemic: Those people who have microfilariae (Mf) in their bloodstream and generally showed no outward signs of filarial disease.
2) Chronic patients: The second group of individuals displayed chronic pathology, such as lymphoedema, hydrocele and elephantiasis. Individuals of this group are generally amicrofilaraemic.
3) Endemic normal: This group represents the population who, are continually exposed to infective mosquito bites but remain both symptom and Mf-free, suggesting that they may be immune to invading larval infection (Maizels and Lawrence, 1991).
Major problems and challenges for the disease control of LF:
Though effective on larval stages, mass drug administrations (MDA) is fairly ineffective at killing adult worms and provide only partial benefit to infected patients. Efforts to alleviate suffering and disability of infected patients focus on hygiene aimed at decreasing secondary bacterial and fungal infection. In 2000, control efforts were formalized as the GPELF by the year 2020 through the distribution of drugs (Molyneux and Zagaria 2002). The aims of this global program are to eliminate transmission of the disease and prevent morbidity in affected individuals through the use of antifilarial drugs in endemic populations (WHO, 1999). The strategies underlying the global programme are well documented and recently reviewed by Ottesen et al., 1997 and Gyapong et al., 2005. These recommended strategies were
(1) MDA with single dose of Albendazole and ivermectin tablets in areas where LF is co-endemic with onchocerciasis for 4-6 years annual,
(2) In non onchocerciasis co-endemic areas single dose annual albendazole and DEC for 4-6 years,
(3) use of DEC tablets or DEC fortified salt for 1-2 years
(4) vector control measures,
(5) home based management of lymphoedema and elephantiasis for affected individuals,
(6) improved access to surgical intervention for men with hydrocele.
The requirement for ongoing annual dosing to prevent the build-up of new larvae from the surviving adult worm is a significant operational challenge in endemic regions subject to poverty and civil unrest. Early diagnosis and treatment play important role to interrupt transmission of infectious diseases and preventing the development of long-term complications. The useful diagnostic methods must be accurate, simple and affordable for the population where they are intended. Despite their importance, diagnostics have been an undervalued component of disease control and prevention.
Diagnosis of LF:
Due to nocturnal periodicity of microfilaria in human blood stream, blood sample should be taken within two hours either side of midnight when the highest density of microfilariae is expected to occur. Simonsen et al., (1997) have devised a method to adjust the effect of sampling time on microfilariae density which helps to predict the microfilariae density at midnight in blood collected at 22:00 hours. The simplest technique for direct diagnosis of microfilaraemia is a thick blood smear methods (Khamboonruang et al., 1987; Schuurkamp et al., 1994) and the number of microfilariae can be calculated in terms of mf/ml in the measured amount of blood such as 40 to 60ul (Moulia-Pelat et al., 1992). However, detection of microfilariae in night blood examination by thick blood smear has some disadvantages; first, it underestimates the prevalence of microfilaraemia at low density (Panicker et al., 1991; Turner 1993) and the second disadvantage is loss of microfilariae from the film during processing especially if anti-coagulated blood is used.
By concentration methods for microfilariae:
To obtain the viable microfilariae, knott concentration method is widely used (knott, 1935). The viable microfilariae can be obtained when citrate-saponin solution is substituted for the 1% formalin solution (McQuay, 1970). The method has been improved by Melrose et al., (2000) in which addition of Triton X-100 dissolves most of the proteinaceous deposit and enhances the visibility of the microfilariae. Another widely used concentration method is the membrane filter technique used where 1ml of blood has been diluted in water and passed through a cellulose filter to trap microfilariae on the filter (Nathan et al., 1981; Moulia-Pelat 1992).
By the DEC provocation test:
DEC can be helpful to detect microfilaria in the day time. A recommended concentration DEC may subjected to provoke the microfilariae to leave the lungs and entering the peripheral circulation where they can be detected by any of the above techniques (who, 1987). The use of this test was discouraged due to its low sensitivity than night blood examination method (WHO, 1987). The other antifilarial drugs ivermectin and albendazole do not induce microfilariae to leave the lungs and enter in the blood circulation during day time (Dunyo et al., 1996).
By detection of filarial antigen:
Filarial antigenicity is associated with active filarial infection (Hamilton, 1985). Several investigators have developed assay for detection of filarial antigens using both polyclonal and monoclonal antibodies raised against various antigens such as in L. corinii, D. immitis, B. malayi, S. digitata (Dasgupta et al., 1984; Hamilton, 1985, Harinath, 1986) and W. bancrofti (Weil and Liftis, 1987). Anti-rabbit B. malayi adult worm antigens can be used for the detection of W. bancrofti microfilaraemic antigen (Hamilton and Scott, 1984). In the earlier reports, polyclonal antibody of B. malayi adult soluble antigen was useful for the detection of filarial antigen in 90-93% of microfilaraemic and 30% of clinical filarial sera (Cheirmaraj et al 1992). Zheng and coworker (1987) showed higher level of filarial antigen detection (>95%) in microfilaraemic and clinical filarial (60%) sera of bancroftian and brugian filariasis using polyclonal antibodies along with a monoclonal antibody raised against B. malayi antigen.
By detection of filarial antigen in body fluids other than blood:
Needham et al (1996) showed a novel approach for potential filarial diagnosis through the detection of antibodies in saliva. The saliva sample can be used for detection of filarial antigens with similar method used for blood, but this would be a much less invasive test than blood collection and would not expose health workers to the danger of blood-borne pathogens such as HIV and hepatitis B and C. Das and coworker (1987) reported the use of urine sample for detection of potential filarial antigen. This anomaly is thought to be caused by the formation of antigen - antibody complexes in the circulation (Das et al. 1987), which should not interfere with detection of filarial antigen by Trop Bio test however as that assay includes a procedure to disassociate antigen - antibody complexes (More and Copeman, 1991).
By detection of filarial-specific enzymes:
Filarial-specific enzymes have been characterized and showed their diagnostic potential either as antigen for antibody assays or by the detection of the enzyme itself. Earlier Mishra et al. (1993) have identified filarial acetylcholinesterase in serum of microfilarial infected peoples. Filarial Glutathione binding proteins, Glutathione-stransferase, proteinases and superoxide dismutase have been detected in the serum of filarial-infected cattle and humans (Beuria et al., 1995) and the latter has been shown to be strongly antigenic.
By filarial antibody assays:
The filarial specific antibody can be detected by various methods like complement fixation, indirect haemagglutination, gel diffusion, immunoelectrophoresis, counter current immunoelectrophoresis, indirect immunofluorescence and enzyme-linked immunosorbent assay (ambroise-thomas, 1980).
Fortunately, there is marked cross reactivity between filaroid species (Tandon et al., 1981) and wide range of other crude filarial parasites antigens have been utilized for filarial antibody detection. Many investigators have reported that cross reactivity of Dirofilaria immitis crude antigen with W. bancrofti (Ambroise-Thomas, 1980; Turner et al., 1993) and B. malayi serum (Riyong et al. 2005). Dissanabake and Ismail (1980) reported that antigenic cross reactivity of Setaria digitata with surface antigen of W. bancrofti microfilariae and W. bancrofti infected serum antibody. There are several reports showing that Litmosoides carinii (Tandon et al. 1981; Rajasekariah et al. 1986) and Setaria cervi (Tandon et al. 1981; Almeida et al. 1990; Sharma et al. 1999) cross reacts with human filarial infected individual's sera. Excretory secretory product and surface antigen of Dirofilairae immitis used for the detection of W. bancrofti infection by ELISA (Dekumyoy et al. 2000).
By demonstration of parasite DNA using polymerase chain reaction (PCR): The PCR method has been successfully used for the diagnosis of filarial infection using W. bancrofti and B. malayi DNA. W. bancrofti DNA used in sputum (Abbasi et al. 1996; Abbasi et al. 1999), blood, plasma and urine (McCarthy et al. 1996). The B. malayi DNA in blood used for diagnosis of its active infection (Lizotte et al. 1994; Rahmah et al. 1998). A combination of PCR-ELISA method for detection of filarial DNA has been devised by Fischer et al. (1999).
Because the adult worm is generally considered responsible for the pathogenesis of lymphatic filariasis, considerable effort has gone into the search for a safe and effective macrofilaricidal agent (Ginger, 1986). In the first half of the 20th century, many drugs were tested for activity against adult filarial parasites. The most common Antifilarial drugs are diethylcarbamazine (DEC), ivermectin and albendazole.
1) DEC: For human use, DEC is manufactured primarily as the dehydrogenate citrate salt. The drug is rapidly absorbed from the gastrointestinal tract and reaches peak levels in the blood within 1-2 hours after an oral dose of 50 mg (Ottesen EA, 1985). The time required for the kidneys to excrete DEC increases with the pH of the urine, but even when the urine is alkaline, the half-life of DEC in the blood is only 10- 12 hours (Ottesen EA, 1985).
2) Ivermectin: Ivermectin, a macrolide antibiotic, is the drug of choice for treatment and control of onchocerciasis. A potent microfilaricidal agent, Ivermectin profoundly suppresses the concentration of W. bancrofti and B. malayi microfilariae in the peripheral blood for periods of 6- 24 months (Dreyer et al. 1995; Kazura et al. 1993; Richards et al. 1991; Eberhard and Lammie 1991; Addiss et al. 1993). Some researcher have hypothesized that ivermectin exerts a macrofilaricidal effect (Ismail et al. 1996), but it is clear from recent ultrasound studies that the adult worms are not killed. For this reason, ivermectin is not the best drug of choice for treatment of individual patients with W. bancrofti or B. malayi infection; however, the drug may play a very important role in community-based control programmes, where lack of local adverse reactions associated with death of the adult worm may enhance community acceptance (Sutanto 1985; Moulia-Pelat 1995).
3) Albendazole: According to Shenoy et al. (1999), this antihelmintic drug is shown to destroy the adult filarial worms when it given twice a day for two weeks. The death of the adult worm induces severe scrotal reactions in bancroftian filariasis since this is the common site where they are lodged (Jayakody, 1993). Albendazole has no direct action against the microfilaria and does not immediately lower the microfilaria counts. When given in single dose of 400 mg in association with DEC or ivermectin, the destruction of microfilaria by these drugs becomes more pronounced. Albendazole combined with DEC or ivermectin is recommended in the global filariasis elimination programmed.
Recent research on the early diagnosis of LF:
As asymptomatic micro?laraemic stage is considered as one of the bottlenecks in the global elimination of LF. Recent study has suggested that, heat shock protein 70 can be a promising agent for immunodiagnosis (Srivastava et. al., 2010). The role of heat shock protein 70 in parasite biology has been reviewed (Srivastava and Rahman, 2014). We have shown that proteomic analysis is very useful in characterizing HSP70 as a disease associated protein, although proteomics was performed in a small cohort which may explore the diagnostic accuracy in the immunodiagnosis of lymphatic ?lariasis in an endemic area. This study also opens a possibility to explore heat shock proteins for their use in the diagnosis of other helminth diseases too.
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I am working as Research Associate in National Institute of Immunology, New Delhi
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