Treating the Disease
Image Album Filariasis
One hundred and twenty million people in at least 80 countries of the world are infected with lymphatic filarial parasites, and it is estimated that 1 billion (20% of the world's population) are at risk of acquiring infection. Ninety percent of these infections are caused by Wuchereria bancrofti, and most of the remainder by Brugia malayi. For W. bancrofti, humans are the exclusive host, and even though certain strains of B. malayi can also infect some feline and monkey species, the life-cycles in humans and in these other animals generally remain epidemiologically distinct, so that little overlap exists. The major vectors for W. bancrofti are culicine mosquitoes in most urban and semi-urban areas, anophelines in the more rural areas of Africa and elsewhere, and Aedes species in many of the endemic Pacific islands. For the Brugian parasites Mansonia species serve as the major vector, but in some areas anopheline mosquitoes are responsible for transmitting the infection. Brugian parasites are confined to areas of east and south Asia, especially India, Malaysia, Indonesia, the Philippines, and China.
Pathogenesis and Pathology
The pathology associated with lymphatic filariasis results from a complex interplay
of the pathogenic potential of the parasite, the immune response of the host, and external ('complicating') bacterial and fungal infections.
While genital damage (particularly hydrocoeles) and lymphoedema / elephantiasis are the most recognizable clinical entities associated with lymphatic filarial infections, there are much earlier stages of lymphatic pathology and dysfunction whose recognition has only recently been made possible through ultrasonographic and lymphoscintigraphic techniques. For example, ultrasonography has identified massive lymphatic dilatation around and for several cm beyond adult filarial worms which, though they are in continuous vigorous motion, remain 'fixed' at characteristic sites within lymphatic vessels.
Filarial infection can be acquired only from vector-borne infective larvae. Therefore, prevention of infection can be achieved either by decreasing contact between humans and vectors or by decreasing the amount of infection the vector can acquire, by treating the human host.
Population: Efforts at filariasis control in populations through reducing the numbers of mosquito vectors have proven largely ineffective. Even when good mosquito control can be put into place, the long life-span of the parasite (4-8 years) means that the infection remains in the community for a long period of time, generally longer than intensive vector control efforts can be sustained. More recently, with the advent of extremely effective single-dose, once-yearly, 2-drug treatment regimens (selecting among albendazole and either ivermectin or diethylcarbamazine [DEC]), an alternative approach has been taken in an initiative being launched through the World Health Organization to utilize a strategy of yearly mass treatment to all "at risk" population to eliminate lymphatic filariasis as a public health problem by decreasing microfilariae in the population, thereby interrupting transmission and preventing infection.
Individuals: Contact with infected mosquitoes can be decreased through the use of personal repellents, bednets or insecticide-impregnated materials. Alternatively, suggestive evidence from animal models and some limited experience in human populations indicate that a prophylactic regimen of DEC (6 mg/kg per day x 2 days each month) could be effective in preventing the acquisition of infection.
There are chronic, acute and 'asymptomatic' presentations of lymphatic filarial disease, as well as a number of syndromes associated with these infections that
may or may or not be caused by the parasites.
Chronic manifestations: Hydrocoele, even though found only with W. bancrofti infections (i.e., not Brugia infections) is the most common clinical manifestation of lymphatic filariasis. It is uncommon in childhood but is seen more frequently post-puberty and with a progressive increase in prevalence with age. In many endemic communities 40-60% of all adult males have hydrocoele. It often develops in the absence of overt inflammatory reactions, and, indeed, many patients with hydrocoele also have microfilariae circulating in the blood. Though the mechanism
of the fluid accumulation in the tunica vaginalis is still unknown, direct ultrasonographic evidence indicates that in bancroftian filariasis the scrotal lymphatics are the preferred site for localization of the adult worms, and their presence may stimulate not only the proliferation of lymphatic endothelium but also a transudation of 'hydrocoele fluid' whose chemical constituents are similar to those of serum. The localization of adult worms in the lymphatics of the spermatic cord leads to a thickening of the cord that is palpable on physical examination of most patients. The hydrocoeles can become massive but still occur without lymphoedema or elephantiasis developing in the penis and scrotum, since the lymphatic drainage of these tissues is separate and more superficial.
Of all the patients with lymphatic filariasis at least half appear clinically asymptomatic, though they have microfilariae circulating in their blood and essentially all have hidden damage to their lymphatic (as evidenced by lymphoscintigraphy) and/or renal systems (microscopic heamaturia and/or proteinuria). It is clear that this state of asymptomatic microfilaraemia is associated with a highly down-regulated immune system, but it is as yet unclear how, when or even whether these individuals will progress to develop one of the more overt clinical manifestations of filarial disease.
A second asymptomatic 'presentation' exists in individuals previously termed 'endemic normals'; their infections are defined not by microfilaraemia but by the presence of parasite antigen in the blood (which will disappear after appropriate treatment). It has only recently been possible to recognize this group of patients, and both their clinical features and sequelae of infection remain to be defined.
Until recently, diagnosis of filarial infection depended on the direct demonstration of the parasite (almost always microfilariae) in blood or skin specimens using relatively cumbersome techniques and having to take into account the periodicity (nocturnal or diurnal) of microfilariae in blood. Alternative methods based on detection of antibodies by immunodiagnostic tests did not prove satisfactory since they both failed to distinguish between active and past infections and had problems with specificity owing to their cross-reactivity with common gastrointestinal parasites and other organisms.
Antigen detection: Circulating filarial antigen (CFA) detection should now be regarded as the 'gold standard' for diagnosing Wuchereria bancrofti infections. The specificity of these assays is near complete, and the sensitivity is greater than that achievable by the earlier parasite-detection assays. Essentially all individuals with microfilaraemia also have detectable circulating antigen, as well as do a proportion of those amicrofilaraemic individuals with clinical manifestations of filariasis (e.g., lymphoedema or elephantiasis) but no circulating microfilariae. In addition, some individuals who appear normal also have detectable circulating antigen that disappears after effective treatment with DEC for these cryptic infections. Two commercial configurations of this assay are available, one based on ELISA methodology that yields semi-quantitative results, and the other based on a simple card (immunochromatographic) test, yielding only qualitative (positive/negative) answers. Thus, this new diagnostic approach is equally applicable to clinical or field evaluation of bancroftian filariasis infections. Unfortunately, no such test is currently available for brugian filariasis.
Prior to the development of the CFA assay, detection of microfilariae in blood was the standard approach to diagnosing lymphatic filarial infection (or loiasis), and it is the one still required today for both brugian filariasis and those situations where the antigen detection test is not available for bancroftian filariasis. For such assessments one must take into account the parasites' possible nocturnal periodicity in selecting the optimal blood drawing time (10 p.m.-2 a.m. for most brugian filariasis and bancroftian infections). The simplest technique for examining blood or other fluids (including hydrocoele fluid, articular effusions and urine) is to spread 20 microliters evenly over a clean slide that is dried and then stained with Giemsa or a similar stain. A wet smear may also be made by diluting 20-40 microliters of anti-coagulated blood with water or 2% saponin, which will lyse the red blood cells but allow the microfilariae to remain motile and thus more readily identifiable. The larger the blood volumes examined, the greater will be the likelihood of detecting low parasitaemias. Knott's concentration technique has been used to examine 1 ml volumes of anti-coagulated blood by mixing the blood with 10 ml of 2% formalin, centrifuging the preparation and examining the sediment either unstained or fixed and stained; the microfilariae are non-motal and generally straight, and they can be easily missed if the viscous sediment is not searched diligently. More recently, membrane filtration has been advanced as the most sensitive technique for detecting and quantitating microfilariae in blood, urine or other body fluids. Polycarbonate (Nuclepore?) filters with a 3 ?m pore size have proved most satisfactory. A known volume of anti-coagulated blood or other fluid is passed through a Swinnex holder containing the filter, followed by a large volume (about 35 ml) of pre-filtered water that lyses the red blood cells. A volume of air then follows the water, and the filter is removed, placed on a slide and stained. Morphology of the parasite is much more difficult to assess than when specimens are prepared initially on slides, but detection and quantitation are very straightforward.
Many lymphatic filariasis patients are amicrofilaraemic, and because no serologic test other than that detecting CFA is specific, in the absence of antigen testing the diagnoses of these infections must be made 'clinically' (i.e., on circumstantial evidence) with support from antibody or other laboratory assays. Most secure of these clinical diagnoses is that of the tropical eosinophilia syndrome; in addition to its distinctive clinical presentation such patients have extraordinarily high levels of total serum IgE (almost always in excess of 10 000 ng/ml), and their levels of specific antifilarial antibodies (both IgG and IgE) are extremely high, the absolute levels depending on the specific tests used. For other amicrofilaraemic syndromes serologic findings based on detecting IgG4 antibodies have proven helpful, since this subclass has greater diagnostic specificity and is stimulated by the presence of active infection. Such antibody analyses are also especially helpful in diagnosing the expatriate syndrome' where 'background (i.e., pre-exposure) levels' of IgG and especially IgG4 antibodies to filarial antigens will be very low, so that elevated levels have significant diagnostic implications in association with the clinical presentations.
Eosinophilia is a frequent concomitant of all filarial syndromes, but only when the levels are extremely high (as in tropical eosinophilia or the expatriate syndrome ) are they diagnostically helpful
Conventional X-rays are rarely helpful in diagnosing lymphatic filarial infection, except in the case of tropical eosinophilia where the picture can be variable but characteristically includes interstitial thickening and diffuse nodular mottling in the lung fields. Ultrasound examination of the lymphatics (especially scrotal lymphatics in men, and the breast and retro-peritoneal lymphatics in women) can reveal rapidly moving ("dancing") adult worms, and lymphoscintigraphy, though not diagnostic of filarial infection, can identify lymphatic functional and gross anatomical abnormalities.
In situations of lymphadenopathy with or without accompanying inflammation of the nodes or lymphatic vessels, biopsy can often detect adult worms, but this approach is rarely used as a diagnostic procedure.
Treating the infection: Remarkable advances in treating lymphatic filariasis have recently been achieved, but most of these have focussed not on the individual but on the community with infection. Thus, the goal has been to reduce microfilaraemia in a community to levels below which successful transmission of infection will not occur. The once-yearly administration of single doses of either 1 or 2 drugs (selecting among ivermectin, DEC and albendazole) to effect this microfilarial reduction has been reviewed above (see 'Prevention'). Few clinical trials, however, have focussed on optimizing treatment of the individual patient, so there is little new data arguing for or against a change from the earlier recommended treatment regimens of DEC (6 mg/kg per day) for 12 days in bancroftian filariasis and for 6 days in brugian filariasis. It is well known that these regimens are not completely effective in eliminating infection, but no intensive studies to determine optimal regimens using the newly available circulating filarial antigen assay or ultrasonographic localization of adult parasites have yet been carried out. Thus, these earlier regimens repeated at 1-6 monthly intervals if necessary, or even the administration of DEC (6-8 mg/kg per day) for 2 days each month for a year are appropriate regimens for treating lymphatic filariasis. Ivermectin, though very effective in decreasing microfilaraemia appears not to kill adult worms (i.e., be macrofilaricidal) and thus can be expected not to cure infection completely. Albendazole can be macrofilaricidal for W. bancrofti if given daily for 2-3 weeks, but optimization of its usage has not been attempted. Thus, for treating infection in individual patients single or repeated courses of DEC are still recommended. However, since the use of DEC in patients with either onchocerciasis or loiasis can be unsafe, it is important that patients with bancroftian filariasis who live in areas endemic for these other infections be examined for co-infection with these parasites before being treated with DEC.
Treating the Disease
While it is important to try to cure the infection itself, management of the consequences of that infection (particularly the lymphoedema, elephantiasis and hydrocoeles) is what is often of greatest concern to the patient. Interestingly, with respect to hydrocoeles it has now been shown repeatedly that treatment of infection in communities with either intermittent (monthly, 6-monthly, yearly) drug administration or the steady use of DEC-fortified table/cooking salt, leads to clinical improvement with decreases in both hydrocoele size and prevalence. Similarly, it is not uncommon to find early lymphoedema regressing completely after treatment of an affected patient with DEC.
In more chronic states, those larger hydrocoeles that do not regress spontaneously or after treatment must be subjected to surgical procedures in order to drain the fluid and render the tunica vaginalis incapable of trapping and retaining it again.
Management regimens should include the following:
Twice-daily washing of the affected parts with soap and water
Raising the affected limb at night
Regularly exercising the affected limb to promote lymph flow
Keeping the nails clean
Use of antiseptic or antibiotic creams to treat small wounds or abrasions.
These same intensive local hygiene efforts and antibiotic ointments can also decrease the frequency of recurrent infection episodes in patients with elephantiasis of the penis or scrotum, but, unfortunately, principles of management have not yet been developed for successfully reversing the anatomic distortions caused by the infection.
Non-invasive management of chyluria relies on nutritional support, especially substitution of foods fat-rich by high protein, high fluid diets supplemented where possible with medium- chain triglycerides. 'Correction' of the lymphatic defect can be effected through surgery, but even the sclerosing effects of lymphangiography or, often, time alone can lead to the cessation of the lymphatic leakage into the renal pelvis collecting system and the urine.
Lymphatic Filariasis, known as elephantiasis, puts at risk more than a billion people in more than 80 countries. Over 120 million have already been affected by it, over 40 million of them are seriously incapacitated and disfigured by the disease. One-third of the people infected with the disease live in India, one third are in Africa and most of the remainder are in Asia, the Pacific and the Americas. In tropical and subtropical areas where lymphatic filariasis is well-established, the prevalence of infection is continuing to increase.
The disease is caused by thread-like, parasitic filarial worms, Wuchereria bancrofti and Brugia malayi, that live almost exclusively in humans. These worms lodge in the lymphatic system, the network of nodes and vessels that maintains the delicate fluid balance between the tissues and blood, and which is an essential component for the body's immune defence system. They live for 4-6 years, producing millions of immature microfilariae (minute larvae) that circulate in the blood, where they may be picked up by mosquitoes, therefore spreading the infection to others.
In its most obvious manifestations, lymphatic filariasis causes enlargement of the entire leg or arm and the genitals (vulva, scrotum and breasts). In endemic communities, 10-50% of men and up to 10% of women can be affected. Even more common than the overt abnormalities is hidden, internal damage to the kidneys and lymphatic system caused by the adult worms, and the disabilities caused by the disease have considerable economic impact on affected communities. The psychological and social stigmata associated with these aspects of the disease are immense too.
The Programme to Eliminate Lymphatic Filariasis has two major objectives:
to stop the spread of filarial infection in all endemic countries; and
to alleviate and prevent the suffering and disability caused by the disease.