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ExtralymphaticBrazilian Journal filarial of Medical and Biological Research (1999) 32: 1467-1472 1467 ISSN 0100-879X Overview

Extralymphatic disease due to bancroftian

G. Dreyer1,2 1Departamento de Parasitologia, Centro de Pesquisas Aggeu Magalhães (CPqAM), P. Dreyer2 and Fundação Oswaldo Cruz, and 2Núcleo de Ensino Pesquisa e Assistência em Filariose W.F. Piessens3 (NEPAF), Hospital das Clínicas, Universidade Federal de Pernambuco, Recife, PE, Brasil 3Department of Immunology and Infectious , Harvard School of Public Health, Boston, MA, USA

Abstract

Correspondence with , , or B. timori not Key words G. Dreyer only affects the structure and function of lymphatic vessels but is also · Wuchereria bancrofti NEPAF, Hospital das Clínicas associated with extralymphatic and disease. Because it is · Microfilaria Universidade Federal de Pernambuco now possible to detect living adult worms by ultrasonography, much · Extralymphatic disease Av. Prof. Moraes Rego, s/n emphasis is placed on lymphatic pathology. However, the finding of · Tropical pulmonary 50670-901 Recife, PE Brasil renal damage in asymptomatic microfilaremic carriers has led to Fax: +55-81-427-6455 increased recognition of the importance of extralymphatic clinical manifestation in bancroftian filariasis. The authors present a number of clinical syndromes that may be manifestations of extralymphatic filarial disease and discuss possible mechanisms that cause these Received July 5, 1999 conditions. The main purpose of this paper is to raise the awareness of Accepted November 8, 1999 students and physicians of the prevalence and the importance of extralymphatic disease in bancroftian filariasis so that it is diagnosed and treated properly and also to alert for the need of additional research in this area.

Introduction fected patients. Lymphatic dysfunction re- sulting from this damage predisposes to local Lymphatic filariasis persists as a major microbial infection, which in turn exacer- cause of clinical morbidity and a significant bates lymphatic pathology (2-5). However, impediment to socioeconomic development little attention has been paid in recent years in Asia, Africa and the Western Pacific, as to clinical manifestations of extralymphatic well as in certain regions of the Americas. It disease caused by filariasis. This paper sum- is estimated that at least 120 million persons marizes the current knowledge about this are infected with W. bancrofti and B. malayi. topic. It is intended to reemphasize the im- Of these, 40 million patients suffer from portance of extralymphatic morbidity in ban- lymphedema, elephantiasis or hydroceles - croftian filariasis, and to highlight the gaps in the well-known clinical manifestations of our knowledge of the pathogenic mechan- lymphatic disease (1). isms that underlie the various clinical syn- Recently, dramatic advances in our un- dromes. derstanding of the of this dis- The extralymphatic syndromes resemble ease have led to the recognition that subclini- clinical entities of nonfilarial origin, and it is cal lymphatic damage is present in all in- often impossible to establish with absolute

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certainty the filarial etiology of extralym- such cases, local release of proteases by the phatic disease manifestations in an infected worms (13) may directly damage synovial individual. Similar diagnostic uncertainties tissue. also apply to some of the “classical” mani- festations of lymphatic filariasis (4,5). Un- Renal disease like lymphatic disease syndromes, the extra- lymphatic manifestations of bancroftian fi- Despite case reports over the years de- lariasis are not caused by adult worms per se, scribing instances of glomerulonephritis, but by microfilariae, by diffusible products hematuria and proteinuria in patients with from as yet undefined parasite stages, or by filarial , the prevalence of renal immune complexes. Extralymphatic filarial abnormalities in bancroftian filariasis has disease is thus heterogeneous in its patho- only recently been formally determined. Re- genesis and clinical manifestations. nal disease is rarely observed in patients without microfilaremia. In contrast, ~45% Arthritis of untreated microfilaremic patients have renal pathology manifested as microscopic Arthritis has long been recognized as a hematuria (~35%) and/or proteinuria (~20%). possible manifestation of filarial infections Treatment with DEC exacerbates the pro- (6). Two clinical types have been described. teinuria in these patients and also triggers The first is oligoarticular “filarial arthritis”, transient hematuria or proteinuria in many a rare condition that typically affects just one microfilaremic persons with a normal urine large joint, most commonly a knee. The en- analysis prior to treatment (14). Mechanical tity can be distinguished from other forms of damage to glomeruli by circulating microfi- arthritis by clinical criteria associated with lariae is believed to account for hematuria in laboratory findings and by its prompt re- some cases (15,16), but damage caused by sponse to (DEC) (7). Its deposition of immune complexes in the glo- pathogenesis is unclear. Synovial fluid from merular basement membrane is likely to be a the affected joint ordinarily does not contain far more common cause of renal pathology microfilariae, adult worms or pyogenic or- in bancroftian filariasis. Such complexes have ganisms, but the monoarticular inflamma- been observed in renal biopsies of patients tion may reflect a tissue reaction to a filarial with filarial infections and glomerulonephri- worm in the vicinity of the joint. Rarely, tis (17-19). However, only in patients with lymphatic fistulation into the synovial sac onchocerciasis has it been formally deter- causes chylous arthritis (8). mined that within immune com- The second manifestation, polyarticular plexes deposited in the kidneys are of filarial “filarial pseudo-rheumatism”, appears to be origin (20). less common in lymphatic filariasis than in onchocerciasis, loiasis or mansonellosis. Its Tropical pulmonary eosinophilia pathogenesis is believed to involve intra- articular deposition of immune complexes Several helminth species can cause pul- (9). However, immune complexes contain- monary infiltrates and eosinophilia (PIE), a ing filarial antigens have yet to be detected in transient syndrome resulting from the migra- synovial tissue, and they are present in sera tion of worms through the organ (21). Fi- from many infected patients without arthritis larial worms most often cause a lingering (10,11). Intact microfilariae have been de- variant of PIE known as tropical pulmonary tected intra-articularly in some patients with eosinophilia (TPE) (22-24). TPE occurs in filarial polyarthritis and in animals (12). In only a small percentage of patients (mostly

Braz J Med Biol Res 32(12) 1999 Extralymphatic filarial disease 1469 males) with bancroftian filariasis (25,26), tively, factors released into the general cir- and nonfilarial helminths can cause a similar culation by filarial worms lodged in extra- clinical syndrome (27). pulmonary lymph vessels may act on lung Filarial TPE is a syndrome clinically char- epithelial cells and cause airway hyperreac- acterized by symptoms of bronchial tivity and/or tissue damage (34). The lung is with paroxysmal nocturnal and ano- the main organ affected by TPE, but extra- rexia. Pulmonary function tests reveal re- pulmonary lesions such as hepatosplenomeg- strictive and obstructive lung disease. Inter- aly and lymphadenopathy can occur (23). stitial lung disease is believed to result from Cardiovascular involvement in TPE has been immune hyperreactivity to microfilaria. Mi- reported (35-38). Because the electrocardio- crofilariae are trapped and destroyed in the graphic changes suggestive of ischemic heart lung by -dependent, cell-mediated disease are reversed following treatment with cytotoxicity involving eosinophils (28). This DEC, it is assumed that carditis is of filarial triggers an inflammatory process that evolves etiology. This may not be true, however, over time. Degenerating worms release so- because in addition to being an antihelmin- matic allergens that bind to specific cell- thic, the drug has anti-inflammatory, antimi- bound IgE and thereby trigger the release of crobial, antifungal and antiviral properties vasoactive and inflammatory molecules by (39-42). lung basophils and mast cells. These media- TPE is the best known clinical manifesta- tors cause some of the allergic asthma-like tion of occult filariasis (43). Destruction of manifestations of TPE. Many empirical and microfilariae in organs other than the lung experimental observations are consistent with can cause several other clinical entities. this model. Microfilariae or recognizable Bonne (44) reported the presence of microfi- fragments are present in lung nodules from lariae and hypereosinophilia in the , patients with TPE and thus may serve to but not in other internal organs, of a man trigger and focus the pathogenic process (29). who died a violent death. The histological Most postulated effector cells and molecules changes in the spleen were similar to those are present in lower respiratory tract epithe- described by Meyers and Kouwenaar (23) in lial lining fluid, i.e., at the site of the lesions lymph nodes from patients with TPE. (30,31). The relationship between filarial worms Microfilariae are a primary trigger of lung and tropical endomyocardial fibrosis (TEMF) disease in the pathogenic scheme just de- remains unclear. The geographic distribu- scribed: the continuous arrival in the lungs tion of TEMF overlaps with that of TPE in of new microfilariae produced by living adult India and with loiasis in Africa, suggesting worms located elsewhere and identified by that eosinophils induced and activated by ultrasonography (27) provides the stimulus filarial infections may cause the observed that guarantees the chronicity of the clinical endomyocardial changes (45). Eosinophils syndrome. However, the effector mechan- have two main functions: they can inactivate isms that damage lung parenchyma are not many of the mediators released by mast cells yet completely known. Possibilities include and thereby dampen tissue reactions associ- immune complex deposition, eosinophil-me- ated with IgE-mediated degranulation of mast diated injury to parenchymal cells and the cells. When activated by or by interstitial matrix (32), cytokine-mediated complement, they can also damage the larval cell injury and other so-called bystander ef- stages of some helminths and kill a variety of fects, as well as possible autoimmune reac- cell types. The damage is inflicted by the tions triggered by crossreactivity between deposition of the contents of the eosino- filarial and human collagens (33). Alterna- philic granule, especially the major basic

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protein (MBP), on the surface of the target II military personnel in the South Pacific worm or cell. It has been suggested that MBP (52,53) and in human volunteers infected release may partly account for the tissue with B. malayi (54), but appear to be rare in damage observed in conditions of local native residents (55). Pathological changes hypereosinophilia such as TEMF. Whether in biopsies from transient rashes in World this has any relevance to the cardiac changes War II soldiers are consistent with an aller- seen in TPE is unknown, but eosinophils gic reaction (56) and markedly differ from from patients with TPE are partly degranu- the inflammatory reactions observed in the lated in vivo (46). skin of patients with chronic lymphedema (3). Some consider these fugitive rashes to Microfilarial granulomata be the equivalents of Calabar swellings (52), i.e., transient areas of angioedema thought to Circumscribed granulomata containing result from an allergic response to Loa loa microfilariae have been observed in the products. Of interest, loiasis in temporary spleen or occasionally in other organs (47,48). residents also often presents with increased However, considering the large number of severity and frequency of pruritus, urticaria microfilariae present in most infected indi- and Calabar swellings compared to the na- viduals, microfilarial granulomata are ex- tive population (57). Thus, immune reac- tremely uncommon and rarely cause clinical tions to filarial worms in immigrants qualita- illness (49). tively and quantitatively differ from those in native residents, perhaps because the latter Filarial splenomegaly develop pre- or perinatal immune tolerance to worm antigens (58,59). The spleen is not usually involved in bancroftian or brugian filariasis although Final considerations splenomegaly occurs in experimentally in- fected animals. Single-dose DEC treatment Infection with lymphatic filarial para- reduced splenomegaly in residents of an area sites is associated with a remarkably wide of Papua New Guinea where bancroftian range of clinical signs, symptoms and se- filariasis and malaria are co-endemic, a find- quelae. Because adult worms are considered ing consistent with the notion that filarial to be the main parasite stage responsible for infection associated with malaria resulted in clinical manifestations of the infection, the higher spleen rates and sizes (50). This does importance of extralymphatic disease mani- not establish a causal relationship between festations has been underrated in the past. W. bancrofti and splenomegaly because DEC The recent recognition that renal damage has many properties besides being an anti- (mainly with microscopic hematuria) is pres- helminthic (see above). Further, reduction ent in 30% of asymptomatic male microfila- of splenomegaly in patients with concomi- remic carriers (14) clearly shows that the tant filariasis and malaria can be achieved by real extralymphatic morbidity might be un- treatment with antimalarials without associ- derestimated worldwide. Hence, as long as ated DEC (51). the lymphatic filariasis elimination program (60) is not completed and microfilariae are Skin rashes not eliminated from carriers, it is advisable that additional studies be conducted in order Transient urticarial skin rashes and non- to improve our knowledge of extralymphatic suppurative swellings without signs of acute disease in endemic areas of lymphatic filari- were observed in World War asis.

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