Brugia malayi is a filarial (arthropod-borne) nematode (roundworm), one of the three causative agents of lymphatic filariasis in humans. Lymphatic filariasis, also known as elephantiasis, is a condition characterized by swelling of the lower limbs. The two other filarial causes of lymphatic filariasis are Wuchereria bancrofti and Brugia timori, which both differ from B. malayi morphologically, symptomatically, and in geographical extent.Johhn, David T., and William A. Petri. Markell and Voge's Medical Parasitology. 9th ed. St. Louis: Saunders Elsevier, 2006.
B. malayi is transmitted by Mansonia mosquitoes and is restricted to South and Southeast Asia. It is one of the tropical diseases targeted for elimination by the year 2020 by the World Health Organization, which has spurred vaccine and drug development, as well as new methods of vector control.
Signs and symptoms
B. malayi is one of the causative agents of lymphatic filariasis, a condition marked by infection and swelling of the lymphatic system. The disease is primarily caused by the presence of worms in the lymphatic vessels and the resulting inflammatory response of the host. Signs of infection are typically consistent with those seen in Bancroftian filariasis—fever, lymphadenitis, lymphangitis, lymphedema, and secondary bacterial infection—with a few exceptions.
Lymphadenitis Lymphadenitis, the swelling of the lymph nodes, is a commonly recognized symptom of many diseases. It is an early manifestation of filariasis, usually occurs in the inguinal area during B. malayi infection and can occur before the worms mature.
Lymphangitis Lymphangitis is the inflammation of the lymphatic vessels in response to infection. It occurs early in the course of infection in response to worm development, molting, death, or bacterial and fungal infection. The affected lymphatic vessels become distended and tender, and the overlying skin becomes erythematous and hot. Abscess formation and ulceration of the affected lymph node occasionally occurs during B. malayi infection, more often than in Bancroftian filariasis. Remnants of adult worms can sometimes be found in the ulcer drainage.
Lymphedema The most obvious sign of infection, elephantiasis, is the enlargement of the limbs–usually the legs. A late complication of infection, elephantiasis is a form of lymphedema and is caused by repeated inflammation of the lymphatic vessels. Repeated inflammatory reactions causes vessel dilation and thickening of the affected lymphatic vessels, which can compromise function. The lymphatic system normally functions to maintain fluid balance between tissues and the blood and serves as an integral part of the immune system. Blockage of these vessels due to inflammatory induced fibrosis, dead worms, or granulomatous reactions can interfere with normal fluid balance, thus leading to swelling in the extremities.. Elephantiasis resulting from B. malayi infection typically affects the distal portions of the extremities. Unlike Bancroftian filariasis, B. malayi rarely affects genitalia and does not cause funiculitis, orchitis, epididymitis, hydrocele, or chyluria, conditions more often observed with Bancroftian infection.
Secondary bacterial infection Secondary bacterial infection is common among patients with filariasis. Compromised immune function due to lymphatic damage in addition to lymph node ulcerations and abscesses exposure and impaired circulation due to elephantiasis can cause secondary bacterial or fungal infection. Elephantiasis, in addition to the physical burden of a swollen limb, can be a severely debilitating condition given bacterial infection. Part of the WHO's "Strategy to Eliminate Lymphatic Filariasis" targets hygiene promotion programs in order to alleviate the suffering of affected individuals (see Prevention Strategies)..
However, clinical manifestations of infection are variable and depend on several factors, including host immune system, infectious dose, and parasite strain differences. Most infections appear asymptomatic, yet vary from individual to individual. Individuals living in endemic areas with microfilaremia may never present with overt symptoms, whereas in other cases, only a few worms can exacerbate a severe inflammatory response.
The development of the disease in humans, however, is not well understood. Adults typically develop worse symptoms, given the long exposure time required for infection. Infection may occur during childhood, but the disease appears to take many years to manifest. The incubation period for infection ranges from 1 month to 2 years and typically microfilariae appear before overt symptoms. Lymphedema can develop within six months and development of elephantiasis has been reported within a year of infection among refugees, who are more immunologically naive. Men tend to develop worse symptoms than women.
Hosts Hosts of B. malayi include Southeast Asian cats.
Cause Life cycle Development and replication of B. malayi occurs in two discrete phases: in the mosquito vector and in the human. Both stages are essential to the life cycle of the parasite.
Mosquito: The mosquito serves as a biological vector and intermediate host – it is required for the developmental cycle and transmission of B. malayi. 4. The mosquito takes a human blood meal and ingests microfilariae (worm-like sheathed eggs) that circulate in the human blood stream. 5-7 In the mosquito, the microfilariae shed sheaths, penetrate the midgut, and migrate to the thoracic muscles were the microfilariae increase in size, molt, and develop into infective larvae (L1 and L3) over a span of 7–21 days. No multiplication or sexual reproduction of microfilariae occurs in the mosquito. 8-1 The infective larvae (L3) migrate to the salivary glands, enter the proboscis and escape onto human skin when the mosquito takes another blood meal.
Human: B. malayi undergoes further development in the human as well as sexual reproduction and egg production. 1-2 The infective larvae (L3) actively penetrate the skin through the bite hole and develop into adults in the lymphatic system over a span of 6 months. Adult worms can survive in the lymphatic system for 5–15 years. 3. The male and female adult worms mate and the females produce an average of 10,000 sheathed eggs (microfilaria) daily The microfilariae enter the blood stream and exhibit nocturnal periodicity and subperiodicity. 4. Another mosquito takes a blood meal and ingests the microfilariae. Infection depends on the mosquito taking a blood meal during a periodic episode – when microfilariae are present in the bloodstream.
Morphology
Adult Adult worms resemble typical nematode roundworms. Long and threadlike, B. malayi and other nematode possess only longitudinal muscles and move in an S-shape motion.. Adults are typically smaller than adult W. bancrofti, though few adults have been isolated. Female adult worms (50 mm) are larger than male worms (25 mm).
Microfilariae B. malayi microfilariae are 200–275 µm in length and have a round anterior end and a pointed posterior end. The microfilariae are sheathed, which stains heavily with Giemsa. The sheath is actually the egg shell, a thin layer that surrounds the egg shell as the microfilariae circulates in the bloodstream. The microfilariae retain the sheath until they are digested in the mosquito midgut.
B. malayi microfilariae resemble W. bancrofti and Loa loa microfilariae with minor differences that can aid in laboratory diagnosis. B. malayi microfilariae can be distinguished by the noncontinuous row of nuclei found in the tip of the tail. There are two terminal nuclei that are distinctly separated from the other nuclei in the tail, whereas the tail of W. bancrofti contains no nuclei and Loa loa microfilariae nuclei form a continuous row in the tail. B. malayi microfilariae also have a characteristic cephalic space ratio of 2:1.
Spread B. malayi is transmitted by a mosquito vector. The principal mosquito vectors include Mansonia, Anopheles, and Aedes mosquitoes. The geographical distribution of the disease is thus dependent on suitable mosquito breeding habitat. The nocturnal periodic form is transmitted by Mansonia and some anopheline mosquitoes in open swamps and rice growing areas. These mosquitoes tend to bite at night and appear to only infect humans. Natural animal infections are rare and experimental animals do not retain infection. The nocturnal subperiodic form is transmitted by Mansonia in forest swamps, where mosquitoes bite in the shade at any time. Natural zoonotic infections are common. Cats, dogs, monkeys, slow lorises, civet cats, and hamsters have all been successfully experimentally infected with B. malayi from man and may serve as important reservoirs.
The accumulation of many infective mosquito bites – several hundreds to thousands – is required to establish infection. This is because a competent mosquito usually transmits only a few infective L3 larvae (see Life cycle), and less than 10% of those larvae progress through all the necessary molting steps and develop into adult worms that can mate. Thus those at greatest risk for infection are individuals living in endemic areas—short term tourists are unlikely to develop lymphatic filariasis.
Diagnosis Tender or enlarged inguinal lymph nodes or swelling in the extremities can alert physicians or public health officials to infection.
With appropriate laboratory equipment, microscopic examination of differential morphological features of microfilariae in stained blood films can aid diagnosis—in particular the examination of the tail portion, the presence of a sheath, and the size of the cephalic space. Giemsa staining will uniquely stain B. malayi sheath pink. However, finding the microfilariae on blood films can be difficult because of the nocturnal periodicity of some forms of B. malayi.
PCR based assays are highly sensitive and can be used to monitor infections both in humans and the mosquito vectors. However, PCR assays are time-consuming, labor-intensive and require laboratory equipment. Lymphatic filariasis mainly affects the poor, who live in areas without such resources..
The ICT antigen card test is widely used in the diagnosis of W. bancrofti, but commercial antigens of B. malayi have not been widely available. However, new research developments have identified a recombinant antigen (BmR1) that is both specific and sensitive in the detection of IgG4 antibodies against B. malayi and B. timori in an enzyme-linked immunosorbent assay and an immunochromatographic rapid dipstick (Brugia Rapid) test. However, it appears that immunoreactivity to this antigen is variable in individuals infected with other filarial nematodes.. This research has led to the development of two new rapid immunochromatographic IgG4 cassette tests – WB rapid and PanLF rapid – which detect Bancroftian filariasis and all three species of lymphatic filariasis, respectively, with high sensitivity and selectivity.
Prevention
Vaccines There is currently no licensed vaccine to prevent lymphatic filariasis. However, recent research has produced vaccine candidates with good results in experimental animals. A glutathione-S-transferase, a detoxification enzyme in parasites isolated from Setaria cervi, a bovine filarial parasite, reduced B. malayi adult parasite burden by more than 82% for 90 days after treatment..
Vector control