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Nine people living in Rhode Island, New York, Pennsylvania, Florida, or California acquired autochthonous brugian filariasis. Each patient had an enlarged lymph node containing a single worm or, in one patient, a pair of worms. Most worms were in lymphatic vessels within the node, but two worms were in the substance of the node. Ten worms were studied, seven female and three male. Female worms contained paired uteri that occupied most of the body cavity of the worm, and male worms contained a single reproductive tract. No worms were gravid. The diameter of the worms was small, 30 micron to 75 micron. The usual diameter of female worms was 65 micron to 75 micron, and 45 micron to 50 micron for male worms. The morphologic features of these worms, their anatomical location, and their geographic distribution are all characteristic of infection with a North American Brugia species.

The effect of intraperitoneal (i.p.) infections induced by inoculations of 30 or 150 Brugia pahangi third-stage larvae (L3) on the development of infections and lymphatic lesions induced by subsequent homologous subcutaneous (s.c.) inoculations were compared in the present study. Lymphatic lesion severity, as judged by the numbers of lymph thrombi present, and lymphatic lesion scores were significantly reduced in both groups of jirds with existing i.p. infections. The numbers of adult worms that developed, locations of these worms, and the subsequent microfilaremias did not differ significantly between groups. All jirds with i.p. infections developed similar antibody titers to crude somatic adult antigen as measured by ELISA. These levels did not change following s.c. infections. Immediate and delayed footpad swelling responses were also similar in all groups. Results of these experiments support and extend previous studies indicating that i.p. infections of B. pahangi induce a hyporesponsive state in jirds to subsequent s.c. infections without significantly affecting the subsequent parasite burden. This effect appears to be independent of the numbers of L3 inoculated i.p. prior to lymphatic-induced infection. Circulating antibody titers and footpad swelling responses to B. pahangi antigen were not reduced in jirds with the hyporesponsive lymphatic inflammatory response and do not correlate with this condition.

Immediate hypersensitivity responses are highly modulated in filariasis, and with few exceptions, the majority of infected individuals do not develop allergic manifestations. One possible mechanism for this modulated responsiveness could involve the high levels of IgG "blocking antibodies" shown to be present in filariasis and other chronic helminth infections. When immunoblot analyses were done to analyze the immunoglobulin (Ig) E and IgG antibody responses of patients simultaneously, remarkable similarity in the patterns of antigen binding was observed. In this study, the four IgG subclasses were analyzed in a similar manner in relation to IgE. The results clearly demonstrate that IgG4 was primarily responsible for this "parallel" recognition that was seen previously between IgG and IgE antibodies. These results lend additional support to the possibility that IgG4 may play an important role in modulating IgE-mediated allergic responses in vivo.

This present study describes the ontogeny and morphology of mononuclear and multinuclear macrophages in murine Brugia pahangi infections. Intraperitoneal infection with L 3 resulted in the development of adult worms and the production of microfilariae in many mice; however, all worms were usually removed by 100 days post infection (p.i.). The infection induced predominantly mononuclear and multinuclear macrophage responses in the peritoneal cavity, with maximum numbers of peritoneal cells being achieved by 8-12 weeks p.i. and at this time some 20% of the macrophages were multinucleated. Lymphocyte numbers were also increased during infection. The reactions around the filariae involved macrophages (both single and multinucleated), eosinophils, fibroblasts and the laying down of collagen. Most worms were involved in these cellular reactions by 5-6 weeks p.i., with the multinuclear macrophages generally seen lying close to the parasites. All stages of parasites developed vacuolar internal changes early in their degeneration with calcification being a later change. The destruction and removal of the sheath was not apparently a prerequisite for degeneration of the body of microfilariae. Rosetting techniques showed that 75% of peritoneal cells (macrophages) in infected animals possessed Fc receptors compared with 32% of those in uninfected mice, and for C3 receptors the respective results were 35% and 5%. The multinuclear cells possessed both types of receptors at levels similar to those of mononuclear macrophages. Likewise both cell types were found to readily phagocytose yeast and latex particles, as well as staining positively for non-specific esterases.(ABSTRACT TRUNCATED AT 250 WORDS)

Microfilaremia, immune responses, and pathology were compared in ferrets infected with 100 third-stage larvae of Brugia malayi (subperiodic strain) or injected intravenously with 10(6) microfilariae. Ferrets (Mustela putorius furo) inoculated with third-stage larvae typically became patent during the third month after infection, with a mean patency of 123 +/- 25 (SE) days. Ferrets injected intravenously with microfilariae exhibited a relatively constant microfilaremia for 3-4 weeks and usually cleared microfilariae before the fourth month. Ferrets that cleared microfilariae after intravenous injection of microfilariae or after infection with third-stage larvae failed to become patent or became amicrofilaremic within 3 weeks after a challenge intravenous injection of 10(6) microfilariae. Clearance of circulating microfilariae was associated with eosinophilia and serum antibody specific for the microfilarial sheath in ferrets injected with microfilariae and in most ferrets infected with third-stage larvae. Ferrets infected with third-stage larvae and necropsied after clearance of microfilariae had tissue inflammatory reactions to microfilariae characteristic of occult filariasis (tropical eosinophilia) in man; these ferrets exhibited immediate cutaneous hypersensitivity and circulating reaginic antibody to antigens of microfilariae. In ferrets necropsied following two intravenous injections of microfilariae, the majority of ferrets examined within 10 days after clearance of microfilariae had visible liver lesions to microfilariae identical to those of the ferrets infected with third-stage larvae; immediate cutaneous hypersensitivity and reaginic antibody were not consistently detected in ferrets injected with microfilariae. Sera from ferrets that had cleared circulating microfilariae were transferred passively into ferrets made microfilaremic by intravenous injection of microfilariae. Sera with microfilarial sheath-reactive IgG antibody titers (greater than or equal to 1:200) and microfilarial agglutination titers (greater than or equal to 1:40) rapidly cleared injected microfilariae (less than 24 hr); this serum also cleared or greatly reduced circulating microfilariae established by an infection with third-stage larvae; only the IgG-containing fraction of the sera was active in immune clearance. Sera that cleared microfilariae of B. malayi did not clear circulating microfilariae of Dirofilaria immitis or prevent recurrence of circulating microfilariae of B. malayi in ferrets infected with adult filariae.(ABSTRACT TRUNCATED AT 400 WORDS)

Infection with filarial nematodes induces lymphatic dysfunction in many individuals in endemic areas. The present morphometric study describes changes in lymphatic endothelial cells of Brugia-infected cats. Transmission electron microscopy revealed a decrease in the number of cytoplasmic vesicles in endothelial cells from lymphatic vessels harboring filarial nematodes (4.9 vesicles per micron 2 cytoplasm) when compared with similar cells from the contralateral uninfected control vessels (9.0 vesicles per micron 2). The size of the vesicles and their location within the cytoplasm was not changed. Irregular large vacuoles, often containing degenerating organelles, were common in endothelial cells lining Brugia-infected lymphatic vessels. These studies suggest that damage of cells by living or dead worms or worm products may have a direct effect on the endothelial lining of lymphatic vessels. This may compromise the efficiency of vessels that collect and transport edematous fluid in affected limbs.

Gravid adult female worms of Wuchereria bancrofti were observed in fine needle aspirates of soft tissue swellings from three patients. An inguinal lymph node was aspirated in two cases, and a breast nodule was the site of aspiration in the third case. In one of the inguinal lymph node aspirates, two adult gravid female worms were identified.

Lymph thrombi in cats experimentally-infected with Brugia malayi were examined by scanning electron microscopy. A variety of morphological forms were noted and it appeared that thrombi undergo a maturation process characterized by at least three transitional phases. Initially, the thrombus consists of erythrocytes encased in fibrin (Phase I). Phase II thrombi are characterized by the appearance of phagocytic cells and fibroblasts on the surface of the thrombus. At the end of the maturation process, the thrombus surface consists solely of fibroblasts or endothelial cells, perhaps derived from the vessel wall (Phase III). Occlusion of the lymphatic lumen by thrombi and the accompanying inflammatory response triggered by B. malayi infection may be a major factor in the pathogenesis of lymph stasis in this disorder.

A case of a 19-year-old inhabitant of Southern India with chronic filarial lymphedema of the right leg and subsequent lymphangiosarcoma is reported. Two additional cases of lymphangiosarcoma occurring in patients with filarial lymphedema are reviewed from the literature.

The quantitative changes of cytoplasmic vesicles and vacuoles in lymphatic endothelial cells of the mongolian jirds associated with Brugia pahangi infections were observed by transmission electron microscopy. The present study revealed a decrease in the proportion of cytoplasm occupied by vesicles and in the number of cytoplasmic vesicles in endothelial cells from lymphatic vessels harboring B. pahangi at 3, 4, and 10 mo after infection (3.55, 3.36, and 2.55 vesicles/micron 2, respectively) when compared with cells from uninfected control vessels (7.03 vesicles/micron 2). On the contrary, there was an increase in the area of vacuoles in endothelial cells of jirds at 3, 4, and 10 mo postinfection. The mean +/- SD diameter of vesicles in cells from lymphatic vessels at 10 mo after infection was significantly smaller (78.6 +/- 5.6 nm) compared to vesicles in uninfected vessels (87.5 +/- 9.7 nm).

Nine new zoonotic Brugia infections, 8 acquired in the United States and 1 in Brazil, are described. In each, a single worm was found in histological sections of lymph nodes or lymphoid tissues. In those from North America, 5 of the 8 worms were females, all were infertile, and only 3 were alive at the time the tissues were excised; all of the patients were male. A dead female worm was collected from a Brazilian male patient. In addition, 3 cases of filarial infections in the U.S., previously identified as Dirofilaria-, Dipetalonema-, or Brugia-like, are reviewed and reclassified as Brugia species on the basis of microscopic morphological features. Morphological features of male and female zoonotic Brugia species as they appear in the host tissues are described. The possible reservoirs of human infections are discussed.

Vaccination of inbred jirds (Meriones unguiculatus) with 60cobalt radiation-attenuated Brugia malayi infective stage larvae (L3) protected against homologous challenge given either subcutaneously (sc) or by the intraperitoneal route (ip). At necropsy numerous nodules were recovered from the peritoneal cavities of jirds which had been vaccinated sc and challenged ip. Histopathologic analysis showed these to be granulomas containing dead and dying larvae and transmission electron microscopy showed that eosinophils were present in high numbers around and within the larvae. Structural damage to the L3 cuticle was apparent in discrete areas and eosinophils actively entering the breached cuticle at the time of fixation were observed. Coalescence of eosinophil secretion granules and the formation of degranulation vacuoles were seen in eosinophils throughout the granulomas. Degranulation resulted in the deposition of electron-dense material on the surface of the larval cuticle. The jird vaccine model for B. malayi thus appears to be a potentially useful tool for investigation of immune mechanisms in filariasis.

A granulomatous inflammatory response develops in jirds with lymphatic or intraperitoneal infections of Brugia pahangi. Light, histochemical, and ultrastructural microscopy were used for comparative studies of the reactions in these 2 locations. The reactions observed were categorized into 3 types: (1) an initial response in which lymphocytes, monocytes, macrophages, and eosinophils were present; (2) an intermediate one which consisted of macrophages, epithelioid cells, lymphocytes, eosinophils, collagen, and mesothelial/endothelial cells with central areas of necrosis; and (3) a terminal reaction consisting of degenerating, necrotic cells. Microfilariae and adult worms were associated with these reactions. Macrophages were the predominant cell type in the lesion and were often found attached to the surface of the parasite. The inflammatory responses to B. pahangi in the lymphatics and in the peritoneal cavity appear to be similar, and thus, the peritoneal cavity may be useful in studying specific cell-parasite interactions to further define the pathogenesis of filarial disease.

The discovery of the silvered leaf monkey, Presbytis cristata, as a suitable experimental host for the human filarial parasite, Wuchereria bancrofti, opened the door for major advances in our understanding of the disease caused by this parasite. To study the pathogenesis of bancroftian filariasis in this model, 15 adult P. cristata which had been experimentally infected with 250 infective third-stage larvae of the parasite were examined. After inoculation with larvae, the monkeys were maintained under study for periods of 2 to 3 years, at which time all had achieved patent infections. At necropsy, Wuchereria-induced macroscopic lesions were not detected in experimentally infected monkeys. Microscopic findings included nematodiasis, microfilariasis, lymphadenitis, lymphangiectasis, perilymphangitis, splenitis, orchitis, periorchitis, epididymitis and funiculitis. Sections of normal adult worms were most often found in lymphatic vessels near lymph nodes, or in the lymphatics of the male genital system. These worms caused microfiliariasis in some regional lymph nodes. Inflammatory responses to filariae were most prominent in proximity to degenerated and dead worms, whereas intact, normal appearing adult worms elicited only minimal cellular response.

Xeroradiographic lymphangiography was carried out at approximately monthly intervals on five dogs during the first 18 weeks following infection with 400 Brugia pahangi infective larvae in the left rear paw. Clinical signs, body temperatures and microfilaria counts were also monitored during this time. Similar observations were made on nine dogs with chronic infections (one to five years duration) of 200 infective larvae in unilateral inguinal sites. Standard thoracic radiography was conducted on all dogs. Surgical occlusion of the major afferent ducts to the popliteal lymph nodes of the infected and noninfected limbs of a chronically infected dog was performed to study oedema induction and resolution. This non-invasive lymphangiographic technique demonstrated marked differences in lymphatic changes among individual dogs. The severity of lymphatic pathology correlated with clinical signs of limb oedema and low microfilaria counts. Chronically infected dogs also demonstrated a variety of pathological manifestations: two dogs presented lymphatic cording and another showed transient lymphadenitis with fever and pulmonary arterial opacities. Surgical occlusion of major lymphatic ducts in an uninfected limb resulted in short-term oedema, while occlusion caused by B. pahangi in acutely infected dogs resulted in more persistent oedema. Surgical occlusion of a major duct in a chronically infected limb did not result in oedema. Xeroradiographic lymphangiography revealed a spectrum of lymphatic pathology in Brugia pahangi-infected dogs and demonstrated the value of this animal model for the study of the pathogenesis of chronic lymphatic filariasis.

The dog infected with Brugia pahangi is an excellent model for studying the clinical and immunological pathogenesis of lymphatic filarial infection and disease. Dogs demonstrated a range of clinical changes including varying levels of microfilaraemia, episodic lymphadenopathy, lymphangitis, and limb oedema similar to the clinical spectrum reported in man. Histologically, tissues from parasite-infected dogs were characterized by fibrosis of the lymph nodes and their afferent and efferent lymphatic ducts in the infected limbs. Some nodes were atrophied while others were characterized by reactive hyperplasia. Duct walls of some afferent lymphatics were thickened with a mononuclear inflammatory infiltrate. Parasite antigen deposition was detected in the subcapsular sinuses and middle of germinal centres of infected popliteal lymph nodes, using an immunohistochemical technique.

Filariasis of the breast is usually seen in endemic areas. Involvement may, however, present years after leaving an endemic area and be associated with circulating microfilariae. We describe the findings in a woman who developed a breast mass three years after a visit to her native India.

Domestic cats and patas monkeys were infected with Brugia malayi so that the worms localized in the regional lymphatics of the hind legs. Reaction to the filarial parasites resulted in visible local edema in cats and disruption of normal lymph flow in the monkeys. Edematous tissue was examined grossly and by light and electron microscopy. Lymph flow patterns were examined by direct observation following injection of lymph staining dye and reflection of the skin, by X-ray following injection of radio-opaque contrast media, and by lymphscintigraphy after subcutaneous injection of radioisotopes. Clinical edema occurred in cats but not in monkeys. However, disruption of normal lymph flow in monkeys infected with Brugia could be demonstrated by lymphscintigraphy.

The development of adult worm burdens and microfilaremias were determined in jirds which received 2, 3, or 4 subcutaneous inoculations of 50 Brugia pahangi infective larvae. Parasite burdens in multiply inoculated jirds were compared to those in four different groups of jirds which received single inoculations of 50 infective larvae. One of each of these singly inoculated groups was infected on the same day that one of the inoculations was given to the multiply infected jirds. Thus, the duration of the infections in the four groups of jirds receiving one inoculation was 54, 118, 189, and 254 days. The development of lymphatic lesions and granulomatous hypersensitivity to B. pahangi antigen was assessed in all jirds at necropsy. The percentage recoveries of adult worms and their locations did not differ in the singly inoculated jirds with infections of different durations. A protective resistance to reinfection, as measured by adult worm recovery in multiply infected jirds, did not occur. The lymphatic lesion scores and numbers of intralymphatic thrombi was greatest in singly inoculated jirds examined 54 days after infection. Pulmonary granuloma areas around adult filarial antigen coated beads embolized in the lungs of jirds 3 days prior to necropsy were also greatest in singly inoculated jirds examined 54 days after infection. Using criteria of lesion scores and lymph thrombi numbers to assess lymphatic lesion severity, a decrease in lesion severity as well as pulmonary granuloma size around antigen coupled beads was seen by 118 days after infection in singly inoculated jirds.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical data on 75 patients, 33 males (44%) and 42 females (56%), with histopathological diagnosis of bancroftian filariasis observed in Recife are presented. The disease predominated in young people. Lymph nodes, especially those of the inguinal region, were the most common site of lesion while the female breast represented the most frequent extra-nodal involvement. The index of clinical suspicion was low, neoplasias being the main preoperatory diagnosis.

After reviewing the main causes of elephantiasis in tropical countries, the results of combined medical and surgical treatment of a case of lymphatic filariasis are reported. Medical treatment consists of a cycle of high-dose mebendazole (40 mg/kg/die) and subsequent cycles of diethylcarbamazine at a habitual dose (6 mg/kg/die). In the interval, the elephantiasic right lip was removed surgically. The overall clinical results was good. Noteworthy was an unwanted, leukopenising side-effect of high-dose mebendazole.

Lymphatic filariasis affects predominantly the poorer sector of a community, who can least afford to have the disease. According to an estimate by the World Health Organization in 1984, more than 90 million people are currently infected. It is postulated that the different disease manifestations of filariasis are caused by different host immune responses. An understanding of the clinical spectrum of lymphatic filariasis is essential for the effective treatment and control of the disease, and for correctly correlating clinical status with host immune responses. The disease should be divided into lymphatic filariasis caused by adult worms and occult filariasis due to hyper-responsiveness of the host against microfilariae. The acute stage of filariasis is characterized by episodic adenolymphangitis, followed by obstructive lesions one or more decades later. In brugian filariasis, adenolymphangitis is most commonly observed at the inguinal region, and elephantiasis predominantly involves the leg below the knee. In bancroftian filariasis, the lymphatics of the male genitalia are frequently affected, leading to epididymo-orchitis and hydrocele. Lymphatic filariasis runs an accelerated clinical course in previously unexposed adult migrants. Occult filariasis is not a disease of public health importance. It is characterized by lymphadenopathy, asthmatic bronchitis, hypereosinophilia, and an increase in the production of antibodies, especially immunoglobulin, against microfilarial antigens.

Immunodeficient nude mice chronically parasitized by subperiodic Brugia malayi developed an elephantoid appearance with persistent lymphoedema of limbs and massive lymphangiectasis of subcutaneous vessels containing viable adult worms. Removal of worms reversed the process. The syndrome was not caused by B. patei or B. pahangi and was not correlated with the presence or absence of microfilaremia. Histologic examination of elephantoid mice revealed dilated and tortuous lymphatics containing small nonobstructive lymph thrombi composed of small mononuclear cells and multinucleate giant cells. Draining lymph nodes were not enlarged or congested and mast cells in oedematous tissue were not degranulated. Analysis of lymph aspirated from dilated lymphatics showed increased total protein content: bacterial sepsis was not detected. This work suggests that viable adult B. malayi exert direct pathologic effects upon lymphatics and that this parasite is more pathogenic than related Brugia spp.