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Acute lymphatic filariasis in an american traveler
DIAGN MICROBIOLINFECTDIS 1992;15:345-347
345
CASE REPORTS
Acute Lymphatic Filariasis in an American Traveler Bonnie Bean, Michael H. Ellman, and Irving G. Kagan
Acute lymphatic filariasis developed in an American traveling recreationally to Asia. The illness was characterized by fatigue, eosinophilia, and lymphedema of the arm and chest wall, but no lymphangitis, lymphadenitis, or pain. Complete
resolution occurred over 1-2 years. We discuss this syndrome and describe the use of new diagnostic tests in its diagnosis and management.
INTRODUCTION
RESULTS
A 45-year-old man was seen 18 November 1988 for fatigue, eosinophilia, and swelling of the left arm and chest, all of 3-4 month's duration. Seven months earlier, in the spring, he had traveled to Nepal--acclimating in Katmandu, then trekking near the base of Mt. Everest. Enroute, both inbound and outbound, he had stayed overnight in Bangkok. He had been out of doors in the evenings, but recalled no mosquito exposure. Physical examination revealed a moderately edematous, warm left arm, especially the medial forearm. Pitting occurred with firm pressure. Mild edema of the left chest wall was also noted; the left hand was normal in size. There was no pain, tenderness, or lymphangitis, no palpable cords or lymph nodes, and no rash. A white blood count revealed modest leukocytosis and marked eosinophilia (Table 1). These findings were similar to those obtained by the patient's primary physician 2 months earlier (Table 1, 10 Sep 88).
A serologic test for filariasis was positive in a titer of 1:256 (indirect hemagglutination, or IHA, using Dirofilaria immitis antigen). No microfilariae were found in blood samples examined at noon and at midnight. Serologic tests were negative for cysticercosis, fascioliasis, strongyloidiasis, toxocariasis, trichinosis, and amebiasis. Stool examinations for ova and parasites were negative. After raking leaves in his yard, the patient developed severe arm and hand swelling, necessitating elevation and pressure wraps. Diethylcarbamazine was administered in a dosage of 2 mg/kg three times daily for 3 weeks. The white blood count and the eosinophils fell rapidly after institution of therapy (Table 1, 29 Nov 88 and 5 Dec 88). They were normal by the end of treatment (22 Dec 88). The fatigue and arm swelling resolved more slowly. Six weeks after therapy (18 Jan 89), the patient was asymptomatic, but the IHA titer was still high and unchanged from the previous two determinations (Table 1). Serologic titers to filariae were then determined by enzyme immunoassay (EIA) utilizing Brugia malayi antigen (Hamilton et al., 1981; Lal and Ottesen, 1988; testing kindly performed by Dr. E. Ottesen, National Institutes of Health). A marked decrease in antibody level was demonstrated (Table 1). Three months later (27 Apr 89), the patient developed slight eosinophilia and an urticarial rash on the arm of 12 hr duration. Nine days after that (5 May 89), the eosinophils were again normal. The IHA titer had also returned to
From the Humana Hospital-MichaelReese (B.B., M.H.E.), Chicago, Illinois;and Parasitic Disease Consultants (I.G.K.), Tucker, Georgia, USA. Address reprint requests to Dr. B. Bean, Departmentof Pathology, Humana Hospital-MichaelReese, 31st at Lake Shore Drive, Chicago, IL 60616, USA. Received 26 March 1991; revised and accepted 5 August 1991. © 1992 Elsevier Science Publishing Co., Inc. 655 Avenue of the Americas, New York, NY 10010 0732-8893/92/$5.00
346
B. Bean et al.
TABLE 1 Hematologic and Serologic Findings in a Patient with Lymphatic Filariasis 10Sep884 White blood cell count (total, per mm3) Neutrophils
18 Nov 88b 29 Nov 88 5Dec88
22 Dec 88
18 Jan 89 27Apr89
5May89
9400
11,100
5700
4200
4200
ND
4600
4700
28
40
52
51
70
ND
54
66
20
15
17
25
26
ND
33
30
48
41
26
16
0
ND
8
1
(%) Lymphocytes
(%) Eosinophils
(%) Antifilarial antibodies IHAc (titer) EIAe (units/ml)
1:256a 2308
1:128" 1962
1:128" 1255
<1:32 ND
aTreatment by primary physician. ~Freatment was instituted 23 Nov 88. "Indirect hemagglutination; normal <1:32 (nonspecific antigen test). ~Sera were run simultaneously in both the EIA and IHA. "Enzyme immunoassay; normal -<150 units/ml (specific antigen test). ND, not done.
normal at that time. Over the next 12 months, the patient experienced four more episodes of mild transient (<24 hr), urticarial eruptions on the arm. They then ceased altogether and he has been well since.
DISCUSSION Our patient had an acute or early form of lymphatic filariasis. This disease was previously described in US servicemen deployed in the South Pacific during World War II (Coggeshall, 1946; Wartman, 1947) and in Indonesians resettled to endemic areas during the 1960s (Partono et al., 1978). The incubation period was 5-18 months, and the illness was characterized by retrograde swelling of an extremity, which was exacerbated by exercise. In the upper extremities, swelling of the medial forearm was especially prominent. Urticaria, a slightly elevated white blood count with marked eosinophilia, and amicrofilaremia were common. Lymphangitis, lymphadenitis, and pain were also noted in most, although not all, of the servicemen. Our case is notable for the absence of these latter findings. Coupled with the chest wall swelling, this suggests that it was the deeper chest wall lymphatics, not the superficial lymphatics of the arm and axilla, that were involved in our patient. Acute lymphatic filariasis is thought to result from limited mosquito exposure and low worm burdens in hosts not previously exposed to filariae (Ottesen, 1989). Clinical disease appears to be due to transient lymphatic obstruction by adult worms and to the host immune response to them, as filariae do not mature, mate, and produce microfilariae in the blood
until 9-12 months following infection (Piessens and Partono, 1980). The disease is characterized by a brisk immune response and a good prognosis, even untreated, as long as exposure ceases (Ottensen, 1989). Long-term sequelae are rare, although mild exacerbations may occur for 10-16 years following infection (Trent, 1963). In contrast, elephantiasis is seen in peoples who live in endemic areas and sustain repeated bites by infected mosquitos. Worm burdens are high in these people, and masses of living and dead filariae eventually obstruct lymphatic channels and nodes, causing chronic lymphedema (Piessens and Partono, 1980). Although tests for filarial antibodies were ultimately helpful, this case also illustrates the difficulties with a serologic diagnosis of helminthic infection. Until recently, antigens from Wuchereria bancrofli and B. malayi were not available, and antigens from more common helminths, such as D. immitis, were used in serologic tests. This resulted in a high frequency of cross reactions. In the IHA, 20%-35% of patients with ascariasis, trichinosis, and schistosomiasis gave false-positive reactions (Kagan et al., 1963). In addition, the sensitivity of the IHA is not good in the early phases of illness, when the predominant antibody type is IgM (Kagan, 1979). Brugia malayi can now be maintained in a rodent model, and specific antigen tests have been developed using this antigen (Hamilton et al., 1981; Lal and Ottesen, 1988). Recently, it has been shown that antibodies to phosphocholine, a polysaccharide antigen found on the surface of diverse microorganisms, accounts for at least some of the cross-reactivity among nematodes (Lal et al., 1987; Lal and Ottesen, 1988). On
Case Report
the basis of this and the fact that h u m a n s make antibodies of the IgG4 subclass to filariae, but not to p h o s p h o c h o l i n e , an i m m u n o a s s a y has b e e n designed to measure IgG4 antibodies to B. malayi, thereby decreasing the n u m b e r of false positives due to crossreactivity (Lal a n d Ottesen, 1988). A l t h o u g h this test had 96% sensitivity in infected patients from endemic areas, it has not b e e n evaluated in those from n o n e n d e m i c areas with limited exposure. E n z y m e i m m u n o a s s a y s for detecting filarial antigens in the blood have also b e e n d e v e l o p e d (Lal et al., 1987; Weil et al., 1987; W e n g e r et al., 1988). T h e y are very sensitive in patients with microfilaremia, but insensitive in those w h o are not microfilaremic. T h e y are also insensitive in the p r e s e n c e of circulating anti-
347
body, which appears to bind the antigen into antig e n - a n t i b o d y complexes (Lal a n d Ottesen, 1989). A l t h o u g h diethylcarbamazine is c o n s i d e r e d standard treatment, recent studies indicate that ivermectin, a synthetic macrolide antibiotic, is also effective as single-dose t h e r a p y for lymphatic filariasis (Ottesen et al., 1990). It m a y not be as effective as diethlcarbamazine for killing adult w o r m s , but the advantage of single-dose administration represents a major advance in the t r e a t m e n t of filariasis.
The authors thank Drs. Mary Lawlor and Calvin Hall for the referral of their patient, and Doris Hart for manuscript preparation.
REFERENCES Coggeshall LT (1946) Filariasis in the serviceman: retrospect and prospect. JAMA 131:8-12. Hamilton RA, Hussain R, Ottesen EA, Adkinson NF Jr (1981) The quantitation of parasite-specific human IgG and IgE in sera: evaluation of a solid phase RIA and ELISA methodology. J Immunol Methods 44:101-104. Kagan IG (1979) Diagnostic, epidemiologic and experimental parasitology: immunologic aspects. Am J Trop Med Hyg 28:429-439. Kagan IG, Norman L, Allain DS (1963) An evaluation of the bentonite flocculation and indirect hemagglutination tests for the diagnosis of filariasis. Am J Trop Med Hyg 12:548-555. Lal RB, Ottesen EA (1988) Enhanced diagnostic specificity in human filariasis by IgG4 antibody assessment. J Infect Dis 158:1034-1037. Lal RB, Ottesen EA (1989) Antibodies to phosphocholinebearing antigens in lymphatic filariasis and changes following treatment with diethylcarbamazine. Clin Exp Immunol 275:52-57. Lal RB, Paranjape RS, Briles DE, Nutman TB, Ottesen EA (1987) Circulating parasite antigen(s) in lymphatic filariasis: use of monoclonal antibodies to phosphocholine for immunodiagnosis. J Immunol 138:3454-3460. Ottesen EA (1989) Filariasis now. Am J Trop Med Hyg 41:917. Ottesen EA, Vijayasekaran V, Kumaraswami V, Pillai SVP,
Sadanandam A, Frederick S, Prabhakar R, Tripathy SP (1990) A controlled trial of ivermectin and diethylcarbamazine in lymphatic filariasis. N Engl J Med 322:11131117. Partono F, Pribadi PW, Soewarta A (1978) Epidemiological and clinical features of Brugia timori in a newly established village, Karakuak, West Flores, Indonesia. Am J Trop Med Hyg 27:910-915. Piessens WF, Partono F (1980) Host-vector-parasite relationships in human filariasis. In Seminars in Infectious Disease, Vol II. Eds, L. Weinstein and BN Fields. New York: Thieme-Stratton, pp 131-152. Trent SC (1963) Reevaluation of World War II veterans with filariasis acquired in the South Pacific. Am J Trop Med Hyg 12:877-887. Wartman WB (1947) Filariasis in American Armed Forces in World War II. Medicine 26:333-394. Weil GJ, Jain DC, Santhanam S, Malhotra A, Kumar H, Sethumadhavan K, Liftis F, Ghosh TK (1987) A monoclonal antibody-based enzyme immunoassay for detecting parasite antigenemia in bancroftian filariasis. J Infect Dis 156:350-355. Wenger JD, Forsyth KP, Kazura JW (1988) Identification of phosphorylcholine epitope-containing antigens in Brugia malayi and relation of serum epitope levels to infection status of jirds with Brugian filariasis. Am J Trop Med Hyg 38:133-141.
345
CASE REPORTS
Acute Lymphatic Filariasis in an American Traveler Bonnie Bean, Michael H. Ellman, and Irving G. Kagan
Acute lymphatic filariasis developed in an American traveling recreationally to Asia. The illness was characterized by fatigue, eosinophilia, and lymphedema of the arm and chest wall, but no lymphangitis, lymphadenitis, or pain. Complete
resolution occurred over 1-2 years. We discuss this syndrome and describe the use of new diagnostic tests in its diagnosis and management.
INTRODUCTION
RESULTS
A 45-year-old man was seen 18 November 1988 for fatigue, eosinophilia, and swelling of the left arm and chest, all of 3-4 month's duration. Seven months earlier, in the spring, he had traveled to Nepal--acclimating in Katmandu, then trekking near the base of Mt. Everest. Enroute, both inbound and outbound, he had stayed overnight in Bangkok. He had been out of doors in the evenings, but recalled no mosquito exposure. Physical examination revealed a moderately edematous, warm left arm, especially the medial forearm. Pitting occurred with firm pressure. Mild edema of the left chest wall was also noted; the left hand was normal in size. There was no pain, tenderness, or lymphangitis, no palpable cords or lymph nodes, and no rash. A white blood count revealed modest leukocytosis and marked eosinophilia (Table 1). These findings were similar to those obtained by the patient's primary physician 2 months earlier (Table 1, 10 Sep 88).
A serologic test for filariasis was positive in a titer of 1:256 (indirect hemagglutination, or IHA, using Dirofilaria immitis antigen). No microfilariae were found in blood samples examined at noon and at midnight. Serologic tests were negative for cysticercosis, fascioliasis, strongyloidiasis, toxocariasis, trichinosis, and amebiasis. Stool examinations for ova and parasites were negative. After raking leaves in his yard, the patient developed severe arm and hand swelling, necessitating elevation and pressure wraps. Diethylcarbamazine was administered in a dosage of 2 mg/kg three times daily for 3 weeks. The white blood count and the eosinophils fell rapidly after institution of therapy (Table 1, 29 Nov 88 and 5 Dec 88). They were normal by the end of treatment (22 Dec 88). The fatigue and arm swelling resolved more slowly. Six weeks after therapy (18 Jan 89), the patient was asymptomatic, but the IHA titer was still high and unchanged from the previous two determinations (Table 1). Serologic titers to filariae were then determined by enzyme immunoassay (EIA) utilizing Brugia malayi antigen (Hamilton et al., 1981; Lal and Ottesen, 1988; testing kindly performed by Dr. E. Ottesen, National Institutes of Health). A marked decrease in antibody level was demonstrated (Table 1). Three months later (27 Apr 89), the patient developed slight eosinophilia and an urticarial rash on the arm of 12 hr duration. Nine days after that (5 May 89), the eosinophils were again normal. The IHA titer had also returned to
From the Humana Hospital-MichaelReese (B.B., M.H.E.), Chicago, Illinois;and Parasitic Disease Consultants (I.G.K.), Tucker, Georgia, USA. Address reprint requests to Dr. B. Bean, Departmentof Pathology, Humana Hospital-MichaelReese, 31st at Lake Shore Drive, Chicago, IL 60616, USA. Received 26 March 1991; revised and accepted 5 August 1991. © 1992 Elsevier Science Publishing Co., Inc. 655 Avenue of the Americas, New York, NY 10010 0732-8893/92/$5.00
346
B. Bean et al.
TABLE 1 Hematologic and Serologic Findings in a Patient with Lymphatic Filariasis 10Sep884 White blood cell count (total, per mm3) Neutrophils
18 Nov 88b 29 Nov 88 5Dec88
22 Dec 88
18 Jan 89 27Apr89
5May89
9400
11,100
5700
4200
4200
ND
4600
4700
28
40
52
51
70
ND
54
66
20
15
17
25
26
ND
33
30
48
41
26
16
0
ND
8
1
(%) Lymphocytes
(%) Eosinophils
(%) Antifilarial antibodies IHAc (titer) EIAe (units/ml)
1:256a 2308
1:128" 1962
1:128" 1255
<1:32 ND
aTreatment by primary physician. ~Freatment was instituted 23 Nov 88. "Indirect hemagglutination; normal <1:32 (nonspecific antigen test). ~Sera were run simultaneously in both the EIA and IHA. "Enzyme immunoassay; normal -<150 units/ml (specific antigen test). ND, not done.
normal at that time. Over the next 12 months, the patient experienced four more episodes of mild transient (<24 hr), urticarial eruptions on the arm. They then ceased altogether and he has been well since.
DISCUSSION Our patient had an acute or early form of lymphatic filariasis. This disease was previously described in US servicemen deployed in the South Pacific during World War II (Coggeshall, 1946; Wartman, 1947) and in Indonesians resettled to endemic areas during the 1960s (Partono et al., 1978). The incubation period was 5-18 months, and the illness was characterized by retrograde swelling of an extremity, which was exacerbated by exercise. In the upper extremities, swelling of the medial forearm was especially prominent. Urticaria, a slightly elevated white blood count with marked eosinophilia, and amicrofilaremia were common. Lymphangitis, lymphadenitis, and pain were also noted in most, although not all, of the servicemen. Our case is notable for the absence of these latter findings. Coupled with the chest wall swelling, this suggests that it was the deeper chest wall lymphatics, not the superficial lymphatics of the arm and axilla, that were involved in our patient. Acute lymphatic filariasis is thought to result from limited mosquito exposure and low worm burdens in hosts not previously exposed to filariae (Ottesen, 1989). Clinical disease appears to be due to transient lymphatic obstruction by adult worms and to the host immune response to them, as filariae do not mature, mate, and produce microfilariae in the blood
until 9-12 months following infection (Piessens and Partono, 1980). The disease is characterized by a brisk immune response and a good prognosis, even untreated, as long as exposure ceases (Ottensen, 1989). Long-term sequelae are rare, although mild exacerbations may occur for 10-16 years following infection (Trent, 1963). In contrast, elephantiasis is seen in peoples who live in endemic areas and sustain repeated bites by infected mosquitos. Worm burdens are high in these people, and masses of living and dead filariae eventually obstruct lymphatic channels and nodes, causing chronic lymphedema (Piessens and Partono, 1980). Although tests for filarial antibodies were ultimately helpful, this case also illustrates the difficulties with a serologic diagnosis of helminthic infection. Until recently, antigens from Wuchereria bancrofli and B. malayi were not available, and antigens from more common helminths, such as D. immitis, were used in serologic tests. This resulted in a high frequency of cross reactions. In the IHA, 20%-35% of patients with ascariasis, trichinosis, and schistosomiasis gave false-positive reactions (Kagan et al., 1963). In addition, the sensitivity of the IHA is not good in the early phases of illness, when the predominant antibody type is IgM (Kagan, 1979). Brugia malayi can now be maintained in a rodent model, and specific antigen tests have been developed using this antigen (Hamilton et al., 1981; Lal and Ottesen, 1988). Recently, it has been shown that antibodies to phosphocholine, a polysaccharide antigen found on the surface of diverse microorganisms, accounts for at least some of the cross-reactivity among nematodes (Lal et al., 1987; Lal and Ottesen, 1988). On
Case Report
the basis of this and the fact that h u m a n s make antibodies of the IgG4 subclass to filariae, but not to p h o s p h o c h o l i n e , an i m m u n o a s s a y has b e e n designed to measure IgG4 antibodies to B. malayi, thereby decreasing the n u m b e r of false positives due to crossreactivity (Lal a n d Ottesen, 1988). A l t h o u g h this test had 96% sensitivity in infected patients from endemic areas, it has not b e e n evaluated in those from n o n e n d e m i c areas with limited exposure. E n z y m e i m m u n o a s s a y s for detecting filarial antigens in the blood have also b e e n d e v e l o p e d (Lal et al., 1987; Weil et al., 1987; W e n g e r et al., 1988). T h e y are very sensitive in patients with microfilaremia, but insensitive in those w h o are not microfilaremic. T h e y are also insensitive in the p r e s e n c e of circulating anti-
347
body, which appears to bind the antigen into antig e n - a n t i b o d y complexes (Lal a n d Ottesen, 1989). A l t h o u g h diethylcarbamazine is c o n s i d e r e d standard treatment, recent studies indicate that ivermectin, a synthetic macrolide antibiotic, is also effective as single-dose t h e r a p y for lymphatic filariasis (Ottesen et al., 1990). It m a y not be as effective as diethlcarbamazine for killing adult w o r m s , but the advantage of single-dose administration represents a major advance in the t r e a t m e n t of filariasis.
The authors thank Drs. Mary Lawlor and Calvin Hall for the referral of their patient, and Doris Hart for manuscript preparation.
REFERENCES Coggeshall LT (1946) Filariasis in the serviceman: retrospect and prospect. JAMA 131:8-12. Hamilton RA, Hussain R, Ottesen EA, Adkinson NF Jr (1981) The quantitation of parasite-specific human IgG and IgE in sera: evaluation of a solid phase RIA and ELISA methodology. J Immunol Methods 44:101-104. Kagan IG (1979) Diagnostic, epidemiologic and experimental parasitology: immunologic aspects. Am J Trop Med Hyg 28:429-439. Kagan IG, Norman L, Allain DS (1963) An evaluation of the bentonite flocculation and indirect hemagglutination tests for the diagnosis of filariasis. Am J Trop Med Hyg 12:548-555. Lal RB, Ottesen EA (1988) Enhanced diagnostic specificity in human filariasis by IgG4 antibody assessment. J Infect Dis 158:1034-1037. Lal RB, Ottesen EA (1989) Antibodies to phosphocholinebearing antigens in lymphatic filariasis and changes following treatment with diethylcarbamazine. Clin Exp Immunol 275:52-57. Lal RB, Paranjape RS, Briles DE, Nutman TB, Ottesen EA (1987) Circulating parasite antigen(s) in lymphatic filariasis: use of monoclonal antibodies to phosphocholine for immunodiagnosis. J Immunol 138:3454-3460. Ottesen EA (1989) Filariasis now. Am J Trop Med Hyg 41:917. Ottesen EA, Vijayasekaran V, Kumaraswami V, Pillai SVP,
Sadanandam A, Frederick S, Prabhakar R, Tripathy SP (1990) A controlled trial of ivermectin and diethylcarbamazine in lymphatic filariasis. N Engl J Med 322:11131117. Partono F, Pribadi PW, Soewarta A (1978) Epidemiological and clinical features of Brugia timori in a newly established village, Karakuak, West Flores, Indonesia. Am J Trop Med Hyg 27:910-915. Piessens WF, Partono F (1980) Host-vector-parasite relationships in human filariasis. In Seminars in Infectious Disease, Vol II. Eds, L. Weinstein and BN Fields. New York: Thieme-Stratton, pp 131-152. Trent SC (1963) Reevaluation of World War II veterans with filariasis acquired in the South Pacific. Am J Trop Med Hyg 12:877-887. Wartman WB (1947) Filariasis in American Armed Forces in World War II. Medicine 26:333-394. Weil GJ, Jain DC, Santhanam S, Malhotra A, Kumar H, Sethumadhavan K, Liftis F, Ghosh TK (1987) A monoclonal antibody-based enzyme immunoassay for detecting parasite antigenemia in bancroftian filariasis. J Infect Dis 156:350-355. Wenger JD, Forsyth KP, Kazura JW (1988) Identification of phosphorylcholine epitope-containing antigens in Brugia malayi and relation of serum epitope levels to infection status of jirds with Brugian filariasis. Am J Trop Med Hyg 38:133-141.