54 Filariasis

The term “filariasis” refers to several diseases of both humans and animals caused by infection with a specific group of parasitic nematodes called filarial worms (named for the hairlike appearance of the adult form).

Distribution and Incidence

Bancroftian filariasis is widely distributed through­out the tropics. Though it no longer exists in areas such as North America (most notably the Charleston,

S.C. area), southern Europe, Australia, and some Ca­ribbean islands, and is decreasing in prevalence in other Caribbean islands, Central America, and South America, W.

Although no precise count of the number of people infected with W. bancrofti exists, in 1984 the World Health Organization estimated that number at more than 81 million. Prevalence is highest in Asia (espe­cially China, India, and Indonesia) and Africa. The disease affects primarily the rural and urban poor of working age living in areas of poor sanitation where mosquitoes abound (Mak 1987; Partono 1987).

Etiology and Epidemiology

The threadlike, white, adult W. bancrofti (males: 40 mm long ? 0.1 mm in diameter; females: 65-100 mm ? 0.2-0.3 mm) lie coiled together in human lymphatic vessels and lymph glands, where they can live for 10 to 18 years. Within 6 months to 1 year of infection, tiny larvae called microfilariae leave the adult female and enter the host’s peripheral blood and lymph channels. Microfilariae move freely through the lymph or blood and, depending on the strain, show nocturnal or diurnal periodicity in the blood. Nocturnal microfilariae (the most common in­fective form) reside in the arterioles of the lungs during the day, whereas the diurnal (also called subperiodic) strain appears in the peripheral blood continuously, although in reduced numbers at night. Geographically, nocturnally periodic microfilariae are generally found west of 140° east longitude, and diurnal microfilariae are present east of 180° east longitude. Both types may be found between these two meridians. The largest concentrations of diurnal microfilariae exist in the Polynesian and New Cale­donian regions of the Pacific Ocean (Sasa 1976; Bea­ver et al. 1984; Manson-Bahr and Bell 1987).

Bancroftian filariasis is transmitted only by mos­quito. There is no known animal reservoir of W. ban­crofti.

Microfilariae have adapted their daily cycles to either day- or night-feeding mosquitoes, depending on the species and activity of these insects in a par­ticular geographic area. The mosquito becomes an intermediate host of microfilariae after taking a blood meal. Microfilariae develop into infective lar­vae within the insect host in less than 2 weeks, and escape from its proboscis onto the skin of the mos­quito’s next human host during feeding. The larvae burrow into the human’s skin through the tiny punc­ture wound and find their way to lymph vessels where they mature within a year and mate, produc­ing more microfilariae (Beaver et al. 1984; Manson- Bahr and Bell 1987).

In a given geographic area, the microfilaria rate (percentage of a given population carrying mi­crofilariae in the peripheral blood), the density of the intermediate host mosquito population, and the presence of a susceptible human population avail­able for repeated bites by infected mosquitoes are key factors in the epidemiology of bancroftian filariasis. The significance of filariasis in an area may be measured by either the microfilaria rate or the actual disease rate (percentage of the population displaying symptoms of filarial infection) (Beaver et al. 1984; Manson-Bahr and Bell 1987).

Clinical Manifestations and Pathology

In nature, only humans develop elephantiasis from filarial infection of the lymphatics, so scientists could not easily study the pathogenesis of ban­croftian filariasis until the recent development of a cat model. As a result of this and other work, re­searchers have described the pathogenesis and pa­thology of bancroftian filariasis more accurately. Filarial disease may not manifest itself for many years despite the presence of microfilaremia.

Once the filarial larva settles in a human lymph channel and begins to mature, it provokes a localized response consisting of lymph vessel dilation and a slowing of lymph flow through that worm-occupied channel. With time the host body responds immuno­logically, sending eosinophils, plasma cells, and macrophages to the sites of infection. Lymphangitis (inflammation of lymph channels) usually results in swelling, redness, and pain, and, when the lymph vessels become hypertrophied, in varices. Fibrosis of the vessel occurs, trapping and killing the adult worm, which is absorbed or calcified. Obliteration of the lymph vessel forces extravasation of lymph into the tissue space, where it accumulates and causes the typical lymphedema of filarial elephantiasis. The swelling can become quite large, consisting of lymph, fat, and fibrotic tissue under tightly stretched and thickened skin (Beaver et al. 1984; Manson-Bahr and Bell 1987).

The clinical course of bancroftian filariasis can follow one of two paths: In highly endemic areas, people are exposed to repeated filarial infections from a very young age. The microfilariae provoke only a weak local tissue response, and the children show little effect of infection. When the larvae move to and then reside in lymph vessels, their hosts in these highly endemic areas do not react with a strong immunologic response (or display severe symptoms), thus allowing new microfilariae to be discharged through the now dilated lymph channels into the blood. The living worms survive for years, producing microfilariae that circulate in their hosts’ blood.

Uninfected adults newly arrived in an endemic region generally show an inflammatory response to filarial infection. American troops in the Pacific dur­ing World War II experienced this problem. Their immune systems reacted quite strongly to the pres­ence of microfilariae in lymphatics, sending a variety of cellular defenders to the affected areas. They sur­rounded the worms, ultimately causing stenosis of the lymphatics. Many soldiers developed very painful swelling of the scrotum, spermatic cord, and arms or legs, as well as orchitis, lymphangitis, and filarial fever (acute fever with headache and symptoms re­sembling malaria, recurring sometimes for years). Such a powerful response generally kills the worm, making it impossible for microfilariae to develop and circulate in the blood, but also causing disruption of the lymphatic system and the early development of elephantiasis. Some researchers believe that ex­treme elephantiasis occurs as a result of secondary infection with streptococcus or other bacteria.

Chronic obstructive filariasis can result in lymph gland enlargement, chyluria (due to obstructed lymph flow to the thoracic duct above the lymphatic branches of the kidney), lymph scrotum (scrotal thickening with lymphatic varicosities), hydrocele, and elephantiasis of the legs, scrotum, labia, arms, or (rarely) breasts (Beaver et al. 1984; Manson-Bahr and Bell 1987; Partono 1987).

Treatment and Control

Several Hiicrofilaricidal drugs exist; the most effec­tive is diethylcarbamazine citrate (DEC), first used in 1947.

Surgical treatment of elephantiasis does not perma­nently cure the problem, though removal of thick­ened skin and extra tissue from the affected area generally relieves the patient’s burden. Pressure ban­daging of affected lower limbs helps reduce swelling.

Once a person is infected with W. bancrofti, progno­sis depends on the extent and nature of the infection, reexposures to the parasite, and the body’s reaction to the infection. Chronic cases have a poor prognosis.

History and Geography

Antiquity Through the Eighteenth Century

The preponderance of evidence indicates that ban- croftian filariasis existed in the ancient tropical world. One can find discussions of something called elephantiasis in the works of many ancient Greek and Roman authors, including Celsus, Galen, Aretaeus, Caelius, Aurelianus, Pliny, and Plutarch. The disease many of them were describing, however, was probably leprosy, which came to be known as elephantiasis graecorum, to distinguish it from an­other form of elephantiasis with a different appear­ance, elephantiasis arabum, probably bancroftian filariasis. Leprosy can cause affected parts of the skin to resemble that of an elephant, but does not cause the scrotal or leg swelling so characteristic of filarial infection.

Bancroftian filariasis was probably not endemic in ancient Italy, Greece, or the Mediterranean region in general, except for certain parts of the Nile Delta. Traders and travelers brought knowledge of the con­dition to residents of the region, and an occasional newcomer undoubtedly carried the disease from his or her home country and suffered from its various manifestations in the Mediterranean region. An­cient descriptions of a medical condition resembling bancroftian filariasis exist not only from Greco- Roman writers but also from people in the Nile Delta, Polynesian islands such as Fiji and the Soci­ety Islands, and India. Late Roman and medieval Arab writers also discussed elephantiasis, the former primarily describing leprosy, and the latter, including Rhazes, Avicenna, and Albucasis, filaria­sis (Adams 1844, 1846, 1847; Bhishagratna, ed. 1911; Castellani 1919; Hoeppli 1959; Foster 1965; Laurence 1967; Sasa 1976).

The historian B. R. Laurence argues that ban- croftian filariasis actually originated in Southeast Asia and spread with the migration of people from that region to the South Pacific islands (especially Polynesia) and to Africa. To survive, the filarial worm adapted its life cycle to the mosquito vectors available in these new areas, thus explaining why W. bancrofti shows both diurnal (i.e., microfilariae present in peripheral blood during the daytime) and nocturnal periodic strains. The elephantiasis de­scribed by early Indian writers, Laurence argues, was actually caused by B. malayi (another filarial worm, much more limited in its distribution) rather than by W. bancrofti. The continued migration of tropical peoples and the opening of the tropical world to trade over the past 300 to 400 years, plus the adaptability of W. bancrofti to a variety of mos­quito vectors, resulted in the spread of the parasite throughout the tropics, including China and India (Laurence 1968, 1977). Filariasis came to the New World, most likely as a result of the African slave trade. That trade, conducted by white Europeans, brought concentrations of infected black Africans to slave depots on West Indian islands like Barbados, where they were sold and redistributed to other West Indian islands, or to the North and South American mainlands. A legacy of this black African slave trade in the United States was the establishment of a focus of bancroftian filariasis at Charleston, South Carolina, and the surrounding “Low Country,” which survived until the early twentieth century (Savitt 1977; Chemin 1987; Reynolds and Sy 1989).

Seventeenth Through Nineteenth Century Seventeenth-, eighteenth-, and nineteenth-century European observers in tropical lands described nu­merous cases of leg and scrotal elephantiasis, and some of endemic hydrocele and of lymph scrotum. A few even recognized and traced the development of elephantiasis from fever through lymphangitis and lymphadenitis, to gradual swelling of a limb or scro­tum. Though these writers located the seat of the disease in the lymphatics, none could identify the cause (Castellani 1919; Laurence 1970). That discov­ery had to await refinements to, and physicians’ acceptance of, the microscope in the latter half of the nineteenth century. Between 1863 and 1900, re­searchers uncovered the basic etiology and epidemi­ology of bancroftian filariasis (Manson-Bahr 1959; Foster 1965; Sasa 1976; Chemin 1983).

The first breakthrough in understanding the cause of elephantiasis occurred in 1863 when a French physician, Jean-Nicolas Demarquay, de­scribed microfilariae (Demarquay 1863). Demar- quay withdrew a milky fluid from the swollen scrotal sac of an 18-year-old Cuban in 1862 and then again a year later. This latter time, viewing the substance under a microscope, he reported: “Atten­tion was drawn above all to a little elongated and cylindrical creature” that “had extremely rapid movements of coiling and uncoiling” (Demarquay 1863). Demarquay and his colleagues found these worms and their eggs in five successive preparations but found none once the scrotal fluid had cooled down. He could not explain the worms’ presence in the microscopic preparation, but hoped that there would be some scientific value for others in publish­ing the case.

Exactly 4 years after Demarquay’s discovery, Otto Eduard Heinrich Wucherer, a Portuguese-born physi­cian of German parentage who practiced in Bahia, Brazil, found “some threadlike worms” in a urinary blood clot of a woman suffering from hematuria (Wucherer 1868). Theodor Bilharz had discovered a worm in Egypt in 1852 that caused hematuria (Schis­tosoma haematobium); Wucherer was investigating the urine of Brazilian hematuria patients to Ieam whether the cause of the disease was the same in the New World. What he saw under the microscope dif­fered greatly from the schistosomes Bilharz had de­scribed. Two years later, after seeing these worms in two more hematuric patients and finding that he could not identify their species from the books on human parasites that he possessed, Wucherer pub­lished his story “as an incentive for some of my colleagues, better qualified and more fortunate than I, to attempt to shed light on a disease, the etiology of which is still enigmatic today” (Wucherer 1868).

In March of 1870, in a different part of the tropical world, India, Timothy Richards Lewis found worms like those Wucherer had described. An 1867 medical graduate of the University of Aberdeen, Scotland, Lewis was treating a 25-year-old East Indian male suffering with chyluria. That patient left the hospital before Lewis could study his condition further, but a second patient, a woman with hematuria and chylous urine, entered the hospital a few days later. Lewis now took a step beyond Demarquay and Wucherer and removed blood from the patient’s finger and stud­ied it microscopically. He found what he called filariae in this blood, just as he found them in the urine. Lewis’s report of these and other patients, pub­lished in 1872, documented for the first time both the presence of microfilariae and the presence of any microorganism in human peripheral blood. He also described, but could not explain, the disappearance of microfilariae from the blood. Lewis (1872) named the organism Filaria hominis sanguinis.

All three of these filarial researchers knew they had identified an immature form of the filarial worm. Nor were they the only ones who saw the microfilariae in chylous urine. Both T. Spencer Cobbold of London and M. Robin of Reunion Island reported similar findings in the early 1870s.

The man who brought together the various bits of knowledge published about human filarial infection and produced a useful theory was Patrick Manson. Bom in Aberdeenshire and an 1866 medical gradu­ate of Aberdeen University, Scotland, Manson spent much of his early professional life, beginning in 1866, as a medical officer in the Chinese Imperial Maritime Customs Service. He treated many Chi­nese elephantiasis patients, recognized and named the condition called “lymph scrotum,” and devised an operation to remove scrotal tumors. During a 1­year leave in England in 1875, he read the available literature on the conditions he had been treating, including descriptions of lymph scrotum in India, the relation of lymph scrotum to elephantiasis, and Lewis’s papers on filarial worms in the blood and lymph of patients with tropical chyluria (Foster 1965). In articles published in 1876 and 1877 in the China Imperial Maritime Customs Medical Reports, Manson presented case studies to show that lymph scrotum, elephantiasis, and tropical chyluria were etiologically related, all caused by the filarial worm described by Lewis, seated in lymphatics (Manson 1876-7). He apparently knew nothing of Demar- quay’s or Wucherer’s articles, published in journals as poorly circulated as the one in which he himself published.

Manson tried in vain to obtain an adult filarial worm from newly deceased patients. Thwarted by the Chinese people’s reluctance to allow autopsies of humans, Manson suggested in print that physicians in India, where the prejudice against dissection was much less, seek out adult worms in patients who had died with these conditions (Foster 1965). The first person to demonstrate the presence of adult filariae in humans practiced, not in India, but in Australia. Joseph Bancroft, an 1859 medical graduate of St. Andrews University in Scotland, moved to Queens­land in 1864 and found a number of patients with lymphatic conditions, though none with elephantia­sis. His first adult worm came from a patient with a lymphatic abscess of the arm. He obtained another four from a hydrocele of the spermatic cord. He for­warded these specimens in 1877 to Cobbold in Lon­don, the leading British helminthologist of the time. The latter published Bancroft’s cover letter with his own commentary in the Lancet (Cobbold 1877). Cobbold had previously encouraged Bancroft to look for the adults after Bancroft sent him, through a former teacher, immature filariae obtained from these patients. It was Cobbold who suggested nam­ing the filarial worm for Bancroft. A co-worker of Wucherer wrote to the Lancet shortly after Cobbold’s article appeared, suggesting that Wucherer de­served credit for discovering the parasite. Both physi­cians were so honored, and the filaria is known as Wuchereria bancrofti (Foster 1965).

How did the worm find its way into humans? Man­son continued his work in China and made a key suggestion in an 1877 essay (not published until 1878), the same year Cobbold announced the discov­ery of the adult worm in human lymphatics (Manson 1877). The Filaria sanguinis hominis embryos, Man­son argued, could not develop, mature, and enter the bloodstream without overwhelming their human host by their sheer number. Using his knowledge of the known life cycles of animal parasites and of certain human parasites, Manson suggested and then demonstrated that the mosquito was the “nurse” of the filarial embryo. The insect ingested filariae in its blood meal and the young worm devel­oped in the body of this second host. When the mos­quito died, usually on stagnant water a few days after feeding, Manson continued, the filariae es­caped into the water and were ingested by humans drinking the now contaminated liquid. The need for a certain mosquito host, in addition to the human host, Manson concluded, explained “the limitation of the distribution of elephantoid diseases to certain districts and zones of the earth’s surface... where the mosquito flourishes” (Manson 1877).

Another filarial mystery remained to be solved: the unpredictable disappearance and reappearance of worm embryos from the blood of patients known to harbor the parasite. Manson employed two assis­tants to take blood around the clock from a filariasis patient. He discovered that the number of micro­filariae grew and shrunk in a regular diurnal pat­tern, the embryos reaching their peak presence in blood in the hours just before and after midnight. He concluded, in his 1879 article (published in 1880), that ^,,[t]he nocturnal habits of the Filaria sanguinis- hominis are adapted to the nocturnal habits of the mosquito, its intermediary host, and is only another of the many wonderful instances of adaptation so constantly met with in nature” (Manson 1879).

What happened to the filariae during the rest of the day? Manson asked that question in his 1879 article but could not answer it for almost another 20 years. In February 1897, Manson, now in London, had the opportunity to study the organs of a patient with filariasis who had committed suicide at 8:30 in the morning, presumably just after the worms would have left the peripheral blood for the day. Postmor­tem examination revealed huge numbers of the em­bryo parasites in the small blood vessels of the lungs and others in the large pulmonary blood vessels (Manson 1899).

Over the next few years, Manson helped revise the answer to a question he had asked in 1877: How did the filariae pass from mosquitoes to humans? Man­son’s earlier answer, that humans ingested them with contaminated drinking water, was challenged shortly after it was suggested. The work of Thomas Bancroft, Joseph Bancroft’s son in Australia, and of Manson’s protege, George C. Low, who used the mos­quito specimens Bancroft sent to Manson, published in 1900, suggested that filarial embryos exited from the mosquito’s proboscis and entered human skin when the insect was in the act of biting (Low 1900). That idea was confirmed by B. Grassi and G. Noe (1900) later that year.

British physicians working in various tropical colonies of the empire had made almost every break­through in uncovering the mystery of filarial infec­tion during the previous 40 years. By 1900 the medical world had a basic understanding of a dis­ease that had plagued and puzzled people since an­cient times.

Todd L. Savitt

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