Filarial Hydrocele

Filariasis has been a known disease for thousands of years. The first documentation of this disease was found in Egyptian papyrus prior to 5000 BC. In 1900, Sir Ronald Ross, a scientist from the Liverpool School of Tropical Medicine, reported that lymphatic filariasis is transmitted through mosquito bites. In 1902, Sir Ross was awarded the Nobel Prize in medicine for his discovery that malaria is transmitted to humans through mosquito bites.

Humans are the definitive host of W bancrofti. Numerous species of mosquitoes from the genera Anopheles, Culex, Aedes, and Mansonia serve as the intermediate host. In infected humans, the adult W bancrofti worms are most commonly found in periaortic, inguinal, and intrascrotal lymphatic tissue.

The microfilariae produced by the female worms enter the bloodstream and are ingested by feeding mosquitoes. Once in the mosquito, the juvenile worms pass through 2 larval stages before development halts. Subsequent blood meals taken by the mosquitoes transmit the third-stage larvae into the human dermis. The juvenile worms then migrate to lymphatic tissue in the infected human, where maturation is completed.

While the adult female worms can continue to produce microfilariae in the human host, the adult worm burden cannot increase in the absence of the intermediate host. In endemic areas, filarial infection begins in childhood and the adult worm burden increases upon repeated exposures. Acute presentations most commonly occur in the fourth or fifth decade of life.

Death of the adult worm causes an inflammatory reaction that manifests as acute filarial lymphangitis (AFL). Granulomatous nodule formation and recurrent episodes of AFL impair lymphatic flow, predisposing the host to secondary bacterial infections, which result in fibrosis, lymphatic obstruction, and lymphedema. High-protein lymphedema causes further inflammation and tissue destruction. Once damage is sufficient to overwhelm the lymphatic system, chronic hydrocele ensues.

Laparoscopic view of enlarged lymphatics secondary to filarial infection.

Recent research has implicated the endosymbiotic bacteria Wolbachia as a possible trigger in the immune reaction following the death of adult worms.[4, 5] Release of these obligate intracellular bacteria by the dead adult W bancrofti worm increases the host’s plasma levels of interleukin (IL)–6, IL-10, lipopolysaccharide-binding protein (LBP), and soluble tumor necrosis factor (TNF)–alpha receptors. The exact role of Wolbachia in lymphatic filariasis and the possibility of novel targets for prevention and treatment, including tetracycline antibiotics, have not been fully studied.

Eight main species of nematodes (roundworms) can cause filariasis; however, the most common is W bancrofti (100 X 0.3 mm), followed by Brugia organisms. The nematodes can live for several years in the lymphatic vessels and lymph nodes. The female worms produce microfilariae (200-300 µm), which circulate in the blood. The microfilariae infect biting Culex pipiens mosquitoes (less commonly Anopheles, Aedes, and Mansonella species). It then develops into the infective filariform larvae within 1-2 weeks. During subsequent bites by the mosquito, the larvae infect human hosts and migrate to the lymphatic tissues, where they develop into adult worms within a year.

Frequency

United States

Bancroftian filariasis is endemic in tropical regions throughout the world. In the United States, the disease may be seen in immigrants from these regions and has been reported in military personnel returning from extended deployment to these areas.

International

The WHO estimates that more than 1.3 billion people in 83 countries and territories are at risk for microfilarial infection. More than 90% of the estimated 120 million infections are due to W bancrofti, of which 26.79 million cases are hydrocele. India bears the greatest burden of this disease, with more than 550 million people at risk. Other endemic areas include the countries of sub-Saharan Africa and Southeast Asia, areas of Latin America, and the Pacific Islands. Prevalence rates of lymphatic filariasis and filarial hydrocele vary. A sample of nearly 5,000 people from 37 districts in Nepal reported a lymphatic filariasis prevalence of up to 40%.[6] A similar study of migrant workers in Myanmar found a prevalence of 2.4%. In endemic countries of Asia and Africa, the prevalence of filarial hydrocele in men older than 45 years commonly exceeds 50%.

Race

No racial predilection for filarial infection has been shown.

Sex

The sexual prevalence of filarial infection varies by region, possibly because of variable exposure in cultural or employment patterns that result in contact with vector species of mosquito.

Age

All ages are susceptible to microfilarial infection. Clinical manifestation and acute presentations of lymphatic filariasis increase in prevalence with age. The prevalence of filarial hydrocele also increases with age.

Established filarial lymphedema is a progressive condition that tends to follow a stable course within 10-15 years of clinical presentation. No medical treatment has been proven to reverse this pathology; therefore, early diagnosis and treatment are of utmost importance.

A review of surgical reconstruction techniques of 48 patients over 10 years demonstrates excellent outcomes.[7]

Although filarial infection in endemic areas is generally acquired in childhood, the disease may take years to manifest before being diagnosed clinically in early adulthood. Therefore, in endemic areas, up to 50% of the population (more commonly men) may have subclinical infection and may develop pathologic sequelae (although rare). This is characterized by the presence of thousands or millions of parasites in the blood. However, this small number of infections in endemic areas with pathologic changes accounts for the bulk of clinical disease.

Many individuals with filarial infection develop fever due to immune reactions. Patients present with episodic fever associated with lymphangitis, lymphadenitis, funiculoepididymitis (ie, inflammation of the spermatic cord and epididymis), transient edema, and small hydroceles. Patients with secondary infections may also present with fever and a purulent reaction.

The hallmark of clinical disease is lymphedema. Patients in the prepatent period (50-150 d) may develop acute lymphedema of the scrotum that remits spontaneously or after medical treatment. In these patients, lymphatic tissues show typical changes of filarial infection, but adult worms are rarely found.

In contrast, patients with established infections develop permanent lymphatic scarring, resulting in progressive lymphedema. The genitals and lower extremities are the areas most commonly affected.

Elephantiasis of the penis and scrotum in patients with filariasis is the most common clinical problem encountered by urologists. Secondary bacterial infections of the skin and local lymph nodes are common in these patients. Although bacteria play no role in chyluria or filarial hydrocele, elephantiasis and lymph scrotum are often superinfected. Bacterial or fungal infections (most commonly streptococci) lead to recurrent lymphangitis, erysipelas, chronic ulcers, or persistent fungal crusting, aggravating the clinical conditions.

Chyluria develops before elephantiasis in young adult patients. Chyluria results from obstruction of the retroperitoneal lymphatic channels, leading to dilatation and rupture in the urinary collecting system. Initially, chyluria may alarm patients; however, subsequently, it may be disregarded. Occasionally, urinary protein loss may be significant and may lead to hypoalbuminemia and anasarca. Most cases of chyluria are intermittent and respond to bed rest and abdominal binders to increase intra-abdominal pressure. Retrograde lymphangiography and lymphosclerosis can be used in an attempt to treat persistent cases.

Filarial hydroceles (see the images below) vary significantly in size. They can grow very large and may become socially unacceptable and cause significant morbidity and discomfort. Differentiating filarial hydrocele from idiopathic hydrocele is difficult in many cases. A history of exposure to infection from traveling to or residency in endemic areas is suggestive. The World Health Organization (WHO) estimates 69% of all hydroceles are filarial in origin. Since the prevalence of hydroceles in non-endemic areas is considerably low, all patients with hydroceles in W. bancroftiendemic areas should be should be examined for other manifestations of filariasis.[8]

Unilateral left hydrocele and testicular enlargement secondary to Wuchereria bancrofti infection in a man who also was positive for microfilariae.

Bilateral hydrocele, testicular enlargement, and inguinal lymphadenopathy secondary to Wuchereria bancrofti infection in a man who also was microfilaremic.

Patients with filarial hydroceles often have a thickened spermatic cord and epididymis with firm nodules. During surgery, the tunica is thickened with calcifications in the wall, and the hydrocele fluid is milky. These findings are uncommon in patients with uncomplicated idiopathic hydroceles. Microfilariae and adult worms are rarely detected in hydrocele fluid.

Lymphocele of the right spermatic cord.

Laboratory tests and findings in filarial hydrocele are as follows:

• Complete blood cell count (CBC): Patients with patent filarial infection commonly have marked eosinophilia

• Serum immunoglobulins: Elevated serum levels of immunoglobulin E (IgE) and immunoglobulin G4 (IgG4) are seen with microfilarial infection

• Enzyme-linked immunoassay (ELISA): Og4C3 monoclonal antibody–based ELISA provides a quantitative measure of circulating filarial antigen (CFA)

• Immunochromatographic testing (ICT): Dipstick testing of whole blood with ICT cards, which utilize monoclonal antibody AD.12, is a qualitative test for CFA that is widely used in the field as a screening test for lymphatic filariasis[9, 10]

• Hydrocele fluid examination: CFA may be detected in hydrocele fluid,[11] and microfilariae may be found on cytology

• Urine examination: Chyluria may be detected macroscopically, and microfilariae may be detected via microscopic examination of voided urine; proteinuria and hematuria may also be seen with microfilarial infection with renal involvement

• Peripheral blood examination: Microfilariae may be detected via microscopic examination of peripheral blood; microfilariae demonstrate a circadian pattern that varies by endemic region, necessitating serum sampling that coincides with periods of activity; activity may be provoked with administration of DEC

Lymphatic obstruction can be demonstrated on ultrasonography. Motile adult worms may be seen in symptomatic and subclinical filarial hydroceles. The characteristic movements of adult filarial worms are called the filarial dance sign (FDS) and are a reliable diagnostic finding. Ultrasonography may also be used to monitor response to treatment.

To guide surgical management, Capuano and Capuano have proposed a standardized clinical classification of filarial hydroceles, based on four criteria[12] :

• Type – Unilateral versus bilateral

• Side (left/right)

• Scrotal enlargement - Rated from I to VI

• Grade of burial of the penis – Rated from 0 to 4

For size of the scrotum, the rating scale is as follows:

• Stage I: Smaller than a tennis ball

• Stage II: Larger than of a tennis ball up and down; the lower pole of the scrotum does not reach halfway down the thigh (between the lower edge of the great trochanter and the upper edge of the patella)

• Stage III: The lower pole of the scrotum reaches the area between mid-thigh and the knee (upper edge of the patella

• Stage IV: The lower pole of the scrotum reaches the area between the upper edge of the patella and the lower edge of the knee (tibial tuberosity)

• Stage V: The lower pole of the scrotum reaches the area between the lower edge of the knee (tibial tuberosity) and the middle of the lower leg

• Stage VI: The lower pole of the scrotum reaches the area between mid-leg and the ankle (bi-malleolar line)

For burial of the penis, which can be assessed with the patient standing or lying down, the rating scale is as follows:

• Grade 0: No apparent burial; penis length is within normal limits

• Grade 1: Partial burial; the length of the visible part of the penis is > 2 cm

• Grade 2: More important partial burial; the length of the visible part of the penis is < 2 cm

• Grade 3: Total burial; the prepuce, or the tip of the glans penis if the patient is circumcised, is visible and flush with the surface of the scrotum

• Grade 4: Total burial; the glans penis is invisible, and the burial cannot be reduced and causes micturition problems

Contrary to the conclusions in previous literature, a 2001 double-blind study in Tanzania found that medical treatment with diethylcarbamazine (DEC) does not affect hydrocele size.[13]

Surgery is the treatment of choice for filarial hydrocele. Indications for hydrocele surgery include the following:

• Medical ineligibility due to untreated hydroceles

• Interference with work

• Interference with sexual function

• Interference with micturition

• Negative impact on the patient’s family

• Dragging pain

• Susceptibility to trauma because of the patient’s work or mode of transport

• Possible effect on the testis of long-standing hydroceles

Because of the scarcity of information regarding surgical treatment of filarial hydrocele, clear contraindications have not been elucidated. Standard contraindications to surgical procedures probably apply.

In 1997, the World Health Assembly (WHA) passed a resolution calling for the initiation of lymphatic filariasis–elimination programs by the governments of endemic areas. By 2013, the Global Programme to Eliminate Lymphatic Filariasis (GPELF) had implemented mass drug administration of the two-drug regimens (diethylcarbamazine [DEC] plus albendazole or ivermectin plus albendazole) or administration of DEC-fortified salt in 60 countries. Since 2000, the program has resulted in the delivery of a cumulative total of 6.2 billion doses of medicine to 1 billion people.[14]

Epidemiological studies indicate that several countries have demonstrated a near-total absence of transmissions as a result of mass drug administration.[14] Programs aimed at alleviating and preventing disability from lymphatic filariasis are also under way.

Subclinical cases should be treated to prevent lymphatic damage because most patients develop full clinical disease. Young adults in endemic areas should be screened for the presence of the parasite and treated if test results are positive.

Diethylcarbamazine

DEC is effective against both microfilariae and adult worms and is considered the drug of choice. It clears the blood of microfilariae, reduces the opportunity for mosquito-borne transmission of the parasite, and reverses filarial-associated hematuria and proteinuria.

DEC does not reverse existing lymphatic damage and does not change the course of pathology in patients with established disease. Patients should be tested every 6-12 months for the presence of the parasite, and patients whose test results are positive should be re-treated.

DEC is only partially effective against adult worms; therefore, ultrasonography of the scrotum should be performed 1 month after treatment; the presence of any residual worms is an indication for re-treatment.

Recommended schedules are 6 mg/kg/d for a total of 72 mg/kg for Wuchereria bancrofti infection and 4 mg/kg/d for a total of 60 mg/kg for infection with Brugia malayi.

DEC causes allergic reactions (Mazzotti reactions), especially in patients with high microfilarial counts. Headache, fever, nausea, vomiting, local pain, and swelling over lymph nodes and along lymphatic vessels have been reported. Therefore, patients with heavy infection should start with low doses (3 mg/kg body weight/d) and gradually increase the dose.

Ivermectin

Ivermectin is a newer antiparasitic drug that causes fewer adverse effects. It has proven to be an effective microfilaricide after a single oral dose of 20-25 mcg/kg of body weight. Because of its low cost, single oral dose, and few adverse effects, it is becoming the drug of choice for early filarial infection. However, ivermectin does not affect adult filarial worms.

Foot care and skin care are essential in patients with lymphedema. Patients should be encouraged to use antiseptic soap to clean their skin daily. Early infections should be treated vigorously.

Combination Therapies

The recommended drug regimen for elimination of lymphatic filariasis outside sub-Saharan Africa is single dose of diethylcarbamazine (DEC) plus albendazole (ALB). Multiple annual treatments are required for elimination since this regimen does not sustainably reduce blood microfilaria (Mf) counts below the threshold required to interrupt transmission. 

Various surgical procedures have been developed to remove the edematous tissue in patients with genital elephantiasis. The principles of these operations follow general plastic-surgery principles. Antibiotics should be initiated the night prior to surgery and continue for a total of 5 days. Analgesics in the form of nonsteroidal anti-inflammatory drugs or oral acetaminophen should be administered as appropriate.

The penile and scrotal skin and subcutaneous tissues can be excised and reconstructed using a partial-thickness graft from normal skin in the upper part of the body without lymphedema. Unmeshed grafts yield a better cosmetic appearance to the penis, while meshed grafts are preferred for scrotal reconstruction. In females, split-thickness grafts can be used to reconstruct the vulva and the perineal skin.

Filarial hydroceles are more difficult to excise surgically than idiopathic hydroceles because of scarring and fibrosis. The ideal procedure is to excise the hydrocele completely with an intact sac. In some cases, this is impossible, and partial excision and eversion of sac edges behind the testis is sufficient.

To determine the appropriate level of care for patients requiring surgical repair, Capuano and Capuano have proposed using their clinical classification of filarial hydrocele (see Clinical). They conclude that a stage I or II hydrocele, associated with grade 0 or 1 penis burial, could be considered a simple hydrocele; surgical treatment is simple, with no anticipated early complications, and can be performed at a level II facility (as defined by the World Health Organization).[12]

A stage III or IV hydrocele associated with grade 2, 3 or 4 penis burial could be considered a complicated hydrocele. These require a longer, more demanding operation and seem to pose a greater risk for complications, so a level III health care facility would be better adapted.[12]

Standard postoperative care applies. Most patients may be discharged home the same day. Patients with undue swelling, pain, or oozing from the wound or those in whom a drain has been placed should be observed for 24-48 hours. Patients should return for a follow-up visit within 7-10 days.

Wound healing is slow and complicated in patients with filariasis because of the lymphedema and chronic scarring. Patients who require excision and grafting of the scrotal or penile skin are at higher risk for graft failure. Wound infections are also common in these patients.

The World Health Organization (WHO) has targeted lymphatic filariasis for global elimination by 2020 by means of mass drug administration (MDA) that uses one of three anti-filarial drug regimens[15] :

• Diethylcarbamazine (DEC) plus albendazole (ALB) in lymphatic filariasis endemic areas outside Africa and in countries within Africa that do not have onchocerciasis or loiasis
• Ivermectin (IVM) combined ALB in African countries that have both lymphatic filariasis and onchocerciasis
• ALB alone in countries that have both lymphatic filariasis and loiasis.

MDA is intended to reduce the microfilariae (Mf) reservoir below a level that is required to sustain transmission of the infection by mosquitoes. Because a single dose of these treatments fails to sterilize or kill all adult filarial worms and reduce the community Mf reservoir to sufficiently low levels, many rounds of MDA are required to interrupt transmission.[15]

Assessing and monitoring changes in filarial lymphedema improves clinical management of patients. The gold standard for measuring limb volume is water displacement (WD). Other methods include tape measures of limb circumference (TMLC) and skin thickness ultrasound (STU). Each examination method has different strengths and weaknesses. WD is the most reliable but also the slowest method and it is difficult to use in patients with advanced lymphedema. TMLC is easier for the patients but is less reliable than WD, and it was relatively labor and time intensive. STU is the difficult method to standardize and the results are operator dependent. 

A promising new option is and infrared three-dimensional imaging (3DI). In a studie of 52 patients with lymphedemao stages 0–6 (N = 28, 19, 20, 21, 2, 4, and 10, respectively), 3DI measurements correlated nearly perfectly with WD (r2 = 0.9945) and TMLC values (r2 > 0.9801). In addition, the infrared 3DI system was much faster, providing volume and circumference measurements for both legs in less than one-tenth of the combined time required for WD and TMLC and it does not require physical contact with the patient, which is important for patients with skin ulcers or infected wounds that are common in patients with advanced lymphedema.[16]