Clinical Features, Diagnosis and Pathology

There are chronic, acute and 'asymptomatic' manifestations of lymphatic filarial disease, as well as a number of syndromes associated with these infections that may or may or not be caused directly by the parasites.

Asymptomatic Presentations 
Less than half the individuals with lymphatic filariasis appear clinically asymptomatic although they have microfilariae circulating in their blood.   However, nearly all have hidden damage to their lymphatic systems (as evidenced by lympho-scintigraphy), and/or renal systems (microscopic heamaturia and/or proteinuria), and possible other systems. It is clear that this state of asymptomatic microfilaraemia is associated with a highly down-regulated immune system.  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 group of individuals previously termed “endemic normals” can now be defined by positive immunological testing although microfilaraemia is absent.  These patients, once treated eventually revert to a negative immunological test. 

Chronic manifestations
Lymphoedema can develop in the absence of overt inflammatory reactions and, in the early stages, is usually associated with microfilaraemia (microfilaria in the peripheral night blood).  The development of lymphoedema is most frequently associated with a history of recurrent inflammatory episodes. Lymphoedema occurs in appendages such as the limbs and breasts, and most commonly in the lower limbs or genitals. In such individuals the early pitting oedema gives rise to a later brawny oedema with hardening of the tissues. Still later, hyper-pigmentation and hyper-keratosis (skin thickening) develop, often with wart-like protuberances which, on histological section, reveal dilated loops of lymphatic vessels within the nodular lesions. Patients with chronic lymphoedema or elephantiasis rarely are microfilaraemic. Very important in the progression of these lesions is that the redundant skin folds, cracks and fissures of the skin provide havens for bacteria and fungi to thrive and intermittently penetrate the epidermis to lead to either local or systemic infections. Sometimes the skin over the nodular protuberances breaks down, causing the dilated lymphatics within to rupture and discharge its lymph fluid directly into the environment, at the same time serving as a  for causeway penetration of bacterial or fungal organisms directly into the lymphatic system. Severe cases can often involve dermal ulceration, and many of these clinically complicated cases have other systemic complications such as diabetes and hypertension.

Hydrocoele, (a fluid filled enlargement of the tissue sac, the tunica vaginalis, around the testicle) even though found only with W. bancrofti infections, is a 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. Hydrocoele 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 ultra-sonographic evidence indicates that in bancroftian filariasis, the scrotal lymphatics are the preferred site for localization of the adult worms.   Their presence may stimulate not only proliferation of the 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 and dilatation  of the cord vessels, which are often  palpable on physical examination. The hydrocoele 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; in the majority of cases the testicle remains intact and relatively unaffected.

Acute manifestations: There are acute manifestations of lymphatic filariasis, each with a potentially different set of causal mechanisms and pathogenic implications.

Adenolymphangitis (ADL): Manifestations of ADL are acute inflammatory episodes of the limbs or scrotum that are probably related to bacterial or fungal secondary infection of tissues with already-compromised lymphatic function. In the past these were termed 'filarial fevers' and more recently 'adenolymphangitis' (ADL).  These infections start peripherally in the skin and have features of cellulitis and drain centrally towards lymph nodes. 

A further manifestation described in the past as 'filarial fever' was caused by inflammation in the lymph node (commonly the inguinal node) with 'retrograde' extension down the lymphatic tract and an accompanying 'cold' oedema. Here the inflammation appears to be immune-mediated, in response to an adult worm dying or being killed in the lymphatic tract. Such immune-mediated reactions are now recognized to be much less frequent (10-20%) than the episodes of inflammation initiated by dermal infection.

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.

Genital damage (specifically hydrocele) 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. Ultrasonography has identified massive lymphatic dilatation around adult filarial worms.  This dilatation can extend several centimetres beyond these worm “nests”.  The adult worms although in continuous vigorous motion, appear to remain 'fixed' at characteristic sites within lymphatic vessels.

View animated documentation of the filaria dance sign (FDS) in bancroftian filariasis 

Diagnosis
Individual diagnosis: Since lymphatic filariasis does not always result in clinical symptoms, the most accurate way to determine if someone is infected is a blood test. In most parts of the world, the parasites have a "nocturnal periodicity" that restricts their appearance in the blood to only the hours of 10pm - 2am. Therefore, the diagnosis of lymphatic filariasis traditionally has depended on the laboratory examination of blood taken between 10pm and 2am when microfilariae are most common in peripheral blood. Besides "night blood films" blood taken at night can be tested by filtration or concentration techniques that are more sensitive as more blood can be taken.  See further reading

Alternative methods based on detection of antibodies by immunodiagnostic tests did not prove really satisfactory since they were not able 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 the most common Wuchereria bancrofti infections. The specificity of this assay is excellent, 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 do a proportion of those amicrofilaraemic individuals with clinical manifestations of filariasis (e.g., lymphoedema or elephantiasis) but have no circulating microfilariae. In addition, some individuals who appear normal also have detectable circulating antigen that disappears after effective treatment for these cryptic infections. A commercial configuration,  Filarial Test Strip (FTS), of this assay is available based on ELISA methodology that yields semi-quantitative results, yielding only qualitative (positive/negative) answers. The FTS is equally applicable to clinical or field evaluation of bancroftian filariasis infections and can be purchased or obtained from WHO for LF surveys.

Filariasis Test Strip (FTS)
The Filariasis Test Strip developed by AlereTM is a rapid diagnostic tool used for the qualitative detection of Wuchereria bancrofti antigen in human blood samples collected by finger stick. Although the test is relatively simple to use, adequate training is necessary to reduce inter-observer variability and to reduce the misreading of strips.

Basic Guidelines

Kits should be stored at 2-37°C. Test strips should NOT be frozen. The AlereTM Filariasis Test Strip kit is stable until the expiration date marked on its outer packaging when stored as specified.  Kits should NOT be used past the expiration date.   

Before beginning field surveys, two strips from each lot of kits should be tested using a positive control that can be obtained from the Filariasis Research Reagent Repository Center (www.filariasiscenter.org (link is external)). DO NOT use strips that are negative when tested with the control. 

When transporting strips for use in the field, a cool box is not required. However, care should be taken not to expose strips to extreme heat for prolonged periods of time.

Strips must be read using bright unfiltered light.  Faint lines can be difficult to see when lighting is not adequate. This is especially important when reading strips at night.  

More detailed information can be found at:

http://who.int/neglected_diseases/news/new_test_enhance_global_lf_elimin...

https://www.youtube.com/watch?v=oB04WgBrGdo&feature=youtu.be

http://www.ntdsupport.org/resources/filariasis-test-strip-bench-aid

http://www.ntdsupport.org/resources/video-how-use-alere-filariasis-test-...

Unfortunately, no antigen test is currently available for brugian filariasis although an antibody test (Brugia Rapid test) does exist and this is in fact useful for detecting the presence of actual and or previous infection and is useful in the community diagnosis.

Clinical Diagnosis
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

Tropical eosinophilia: 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.

Imaging Techniques
X-rays Diagnosis: 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: 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 (see 'Animated documentation of the filaria dance sign (FDS) in bancroftian filariasis' in Filaria Journal (link is external)).

Lymphoscintigraphy: lymphoscintigraphy, though not diagnostic of filarial infection, can identify lymphatic functional and gross anatomical abnormalities.

Biopsy
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.