Weinke, Thomas Loscher, Klaus Fleischer, Harald Kretschmer, Hans D. Pohle, Bernd. Kohler, Thomas Schlunk, Ralf Clemens, and Hans L. Bock. 1.
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Copyright c 1992, by The American Society ofTropical Medicine and Hygiene Made in USA
THE AMERICAN JOURNAL OF
TROPICAL MEDICINE AND HYGIENE VOLUME 47
JULY 1992
NUMBER 1
CONTENTS Boutonneuse Fever — 78 Capillariasis — 10 Chagas' Disease — 20 Chikungunya Virus — 98 Giardiasis — 13 Japanese B Encephalitis — 61 Leishmaniasis — 47, 87, 117 Lyme Disease — 55
Lymphocytic Choriomeningitis — 27 Malaria - 1,41, 108, 112 Paragonimiasis — 104 Plague - 92 Q Fever - 35 Schistosomiasis — 6 Trichomonas vaginalis — 70
In this issue
iii
TRAVEL MEDICINE The efficacy of halofantrine in the treatment of acute malaria in nonimmune travelers—Thomas Weinke, Thomas Loscher, Klaus Fleischer, Harald Kretschmer, Hans D. Pohle, Bernd Kohler, Thomas Schlunk, Ralf Clemens, and Hans L. Bock
1
Schistosomiasis and the Dogon country (Mali)—M. Corachan, L. Ruiz, M . E. Valls, and J . Gascon
6
Intestinal capillariasis ( C a p i l l a r i a p h i l i p p i n e n s i s ) acquired in Indonesia: a case report—Guido Chichino, Anna Maria Bernuzzi, Antonella Bruno, Claudia Cevini, Chiara Atzori, Antonello Malfitano, and Massimo Scaglia
10
EPIDEMIOLOGY Epidemiology of giardiasis in Wisconsin: increasing incidence of reported cases and unexplained seasonal trends—David G. Addiss, Jeffrey P. Davis, Jacquelin M . Roberts, and Eric E . Mast
13
Vectorial transmission of Trypanosoma c r u z i : an experimental field study with susceptible and immunized hosts—S. S. Catala, D. E. Gorla, and M . A. Basombrio
20
Lymphocytic choriomeningitis virus infection and house mouse { M u s musculus) distribution in urban Baltimore—James E. Childs, Gregory E. Glass, George W. Korch, Thomas G. Ksiazek, and James W. LeDuc
27
A Cluster of C o x i e l l a b u r n e t i i infections associated with exposure to vaccinated goats and their unpasteurized dairy products—Daniel B. Fishbein and Didier Raoult
35
Ookinete rates in Afrotropical anopheline mosquitoes as a measure of human malaria infectiousness—John C. Beier, Robert S. Copeland, Ramadhan Mtalib, and Jefferson A. Vaughan
41
Epidemiologie investigation of an outbreak of cutaneous leishmaniasis in a defined geographic focus of transmission—Jose L. Sanchez, Benedict M . Diniega, James W. Small, Richard N. Miller, Jose M . Andujar, Peter J . Weina, Phillip G. Lawyer, W. Ripley Ballou, and James K. Lovelace
47
Clustering of host-seeking nymphal deer ticks {Ixodes d a m m i n i ) infected by Lyme disease spirochetes { B o r r e l i a burgdorferi)—Sam R. Telford III, Sandy S. Urioste, and Andrew Spielman
55
MOLECULAR/BASIC BIOLOGY A new genotype of Japanese encephalitis virus from Indonesia—Woan-Ru Chen, Rebeca RicoHesse, and Robert B. Tesh
61
Characterization of the heat-shock response of T r i c h o m o n a s vaginalis—Sara William B. Lushbaugh
70
Antigenic diversity of R i c k e t t s i a conorii—David Li, Catherine Taylor, and Hui-min Feng
R. Davis and
H . Walker, Qing-huai Liu, Xue-jie Yu, Han
Nucleoside transporters in L e i s h m a n i a m a j o r : diversity in adenosine transporter expression or function in different strains—Hans P. Baer, Vincent Serignese, Patrick O. J . Ogbunude, and Maud Dzimiri
78
87
IMMUNOLOGY/V ACCINES Failure of intragastrically administered Y e r s i n i a pestis capsular antigen to protect mice against challenge with virulent plague: suppression of fraction 1-specific antibody response—Rex E. Thomas, Warren J . Simpson, Linda L. Perry, and Tom G. Schwan
92
Limited potential for mosquito transmission of a live, attenuated Chikungunya virus Vaccine— Michael J . Turell and Frank J . Malinoski
98
Parasite-specific IgE and IgG levels in the serum and pleural effusion of Paragonimiasis westermani patients—Teruaki Ikeda, Yosaburo Oikawa, Makoto Owhashi, and Yukifumi Nawa
104
DRUG STUDIES Quinine with tetracycline for the treatment of drug-resistant falciparum malaria in Thailand— George Watt, Lersan Loesuttivibool, G. Dennis Shanks, Ellen F. Boudreau, Arthur E. Brown, Katchrinnee Pavanand, H . Kyle Webster, and Suwit Wechgritaya
108
Emergence of multidrug-resistant P l a s m o d i u m f a l c i p a r u m in Thailand: in vitro tracking— Chansuda Wongsrichanalai, H . Kyle Webster, Theera Wimonwattrawatee, Prasit Sookto, Niphon Chuanak, Krongthong Thimasarn, and W. H . Wernsdorfer
112
Drug resistance in leishmaniasis: its implication in systemic chemotherapy of cutaneous and mucocutaneous disease—Max Grogl, Tina N. Thomason, and Eileen D. Franke
117
Number 6 (June) of Volume 46 was mailed to subscribers on 30 June 1992
A m . J. Trop. Med. Hyg., 47(1), 1992, pp. t-5 Copyright © 1992 by The American Society ofTropical Medicine and Hygiene
T H E E F F I C A C Y OF H A L O F A N T R I N E I N T H E T R E A T M E N T OF A C U T E M A L A R I A I N N O N I M M U N E T R A V E L E R S T H O M A S W E I N K E , T H O M A S L O S C H E R , K L A U S FLEISCHER, H A R A L D K R E T S C H M E R , H A N S D. P O H L E , B E R N D K O H L E R , T H O M A S S C H L U N K , R A L F C L E M E N S , A N D H A N S L. B O C K U n i v e r s i t a t s k l i n i k u m R u d o l f V i r c h o w , I I M e d i z i n i s c h e K l i n i k , B e r l i n , G e r m a n y ; A b t e i l u n g für I n f e k t i o n s u n d T r o p e n m e d i z i n der Universität, München, G e r m a n y ; M i s s i o n s a r z t l i c h e K l i n i k , Tropenmedizin, Wurzburg, Germany; Tropenklinik Paul-Lechler-Krankenhaus, Tubingen, Germany; S m i t h K l i n e Beecham, K l i n i s c h e F o r s c h u n g , München, G e r m a n y A b s t r a c t . A multicenter prospective trial was performed to investigate the efficacy and the tolerability o f halofantrine i n n o n i m m u n e patients with malaria imported from areas w i t h drug-resistant falciparum parasites (mainly Africa). Forty-five o f the 74 subjects were treated with a one-day regimen (3 x 500 mg) of halofantrine, and the other 29 received the same regimen with an additional treatment on day 7. In the second group, a 100% efficacy rate was demonstrated, but i n the group receiving the one-day regimen, four recrudescences were observed i n patients with falciparum malaria. O n l y five m i l d adverse reactions were seen, which disappeared spontaneously after the end o f the treatment. W e conclude that halofantrine is highly effective i n curing malaria i n n o n i m m u n e subjects. The treatment scheme for such persons should include an additional treatment on day 7 for n o n i m m u n e individuals. T h i s drug was well tolerated in our patients, indicating that halofantrine will be useful i n the treatment o f multidrug-resistant malaria i n n o n i m m u n e persons.
The spread of multi-resistant P l a s m o d i u m f a l c i p a r u m strains to many countries where malaria transmission occurs poses a considerable challenge i n the treatment o f infected patients. F u r thermore, severe side effects o f other established antimalarial drugs such as pyrimethamine-sulfadoxine (Fansidar®) or amodiaquine restrict their use for Prophylaxis or treatment. One o f the newer drugs, mefloquine, has been shown to produce moderate to severe neuropsychiatric reactions with a frequency o f 1 i n 215 after therapeutic use; reduced i n vitro sensitivity has also been demonstrated with this drug. Therefore, new drugs that are efficacious and safe are urgently needed.
erability o f halofantrine hydrochloride i n nonimmune patients, and to evaluate the need for a regimen with a repetitive dose after one week.
1
2-5
6
7
Halofantrine, a phenanthrene methanol, is such a new antimalarial drug, and it has been shown to be efficacious i n semi-immune patients i n various endemic a r e a s . Data are scanty o n n o n i m m u n e travelers who have contracted malaria during short term stays i n the tropics and their treatment with halofantrine. In semi-immune persons, a one-day treatment produced excellent results, but recrudescences were reported i n n o n i m m u n e patients. The current study was undertaken to investigate the efficacy and tol8 1 3
14
15
PATIENTS AND METHODS
This multicenter trial was carried out prospectively i n four hospitals i n Germany. Patients who returned from a stay i n the tropics were screened and recruited i f they met the following criteria: 1) they had parasitologic evidence o f parasites i n the blood with clinical Symptoms o f malaria, 2) they were older than 18 years o f age and younger than 65 years o f age, and 3) they were n o n i m m u n e white individuals l i v i n g usually i n Central Europe, or i f the patient is o f African/Asian origin, they must have stayed more than one year outside endemic areas. Written informed consent for participation i n the study was obtained from all patients. Parasite densities were calculated by counting asexual parasites against 5,000 red blood cells on Giemsa-stained thin b l o o d films, or against 200 white blood cells on thick b l o o d films when the parasitemia was < 0.1%. Exclusion criteria were 1) severe or c o m p l i -
2
WEINKE AND
cated malaria (e.g., renal failure, severe Hypotension, central nervous System disorders, v o m i t i n g , fever > 41°C) or a parasite count > 500,000/^1 2) being pregnant or nursing, 3) body weight < 40 kg, and 4) concomitant antimalarial treatment. Forty-five patients were treated orally w i t h halofantrine hydrochloride (3 x 500 m g tablets) within a 12-hr period (group 1). T h e other 29 patients were given the same treatment regimen on day 0 and an additional treatment on day 7 (group 2). N o differences could be observed between the two groups concerning travel destinations. In those w i t h P. vivax malaria, a Standard course o f Primaquine was given after the treatment with halofantrine. A l t h o u g h 80 patients were enrolled i n the study, six were not available for followup examinations, and a judgment o f drug efficacy i n these patients was not possible. The data from these six patients were included only i n the evaluation o f drug tolerability. Efficacy and tolerability evaluations included hematologic examinations (hemoglobin level and white blood cell and platelet counts), clinical b i o chemical tests (levels o f blood urea nitrogen, bilirubin, liver transaminases and a l kaline Phosphatase, and serum electrolytes and glucose), urinalysis (glucose and protein levels), recording of body temperature, and parasite count (parasite density). Hematologic and biochemical values were determined on days 1-5, 7, 14, 21, and 28, urinalysis was performed once a week, and temperatures were recorded twice a day. Parasite counts were obtained before treatment, twice a day until blood smears were negative, and on days 5, 7, 14, 21, and 28. C l i n i c a l investigations were carried out on days 1-5, 7, 14, 21, and 28. Thus, efficacy could be determined w i t h the f o l lowing parameters: eure rate, parasite clearance time (hr), fever clearance time (hr), and recrudescence rate. D r u g tolerability was measured by determination o f the frequency and severity o f adverse reactions.
Creatinine,
RESULTS
The 74 fully compliant subjects (55 men and 19 women) had a mean age o f 35.5 years (age ränge 2 3 - 6 1 ) and a mean body weight o f 72.9 kg (ränge 52-101.8). Sixty-two of the 74 patients (83.8%) were white a n d iived i n Central Europe. Ten (13.5%) were of African origin and two (2.7%)
OTHERS
were o f A s i a n origin, but all had lived i n G e r many for a period o f more than one year. Plasmodium f a l c i p a r u m was detected i n 50 patients and P. vivax i n 20 patients; i n four patients, the Plasmodium species could not be classified because o f very low parasitemias and identification o f parasites on thick smears only. T h e mean pretreatment parasite count was 40, 350/ fA and the parasite density ranged from < 5,000/ Ml to 250,000/^1 (Table 1). The patients had contracted their malaria infections i n sub-Saharan Africa (78%), South A m e r i c a (6%), the Indian subcontinent (6%), and southeast A s i a (10%). M a l a r i a chemoprophylaxis was used by 37 (50%) of the 74 travelers, and consisted mainly of chloroquine (n = 21) or chloroquine plus proguanil (n = 9); 37 (50%) patients d i d not use any chemoprophylactic agent. Pretreatment clinical Symptoms consisted o f fever (n = 71, 95.9%), headache (n = 64, 87%), dizziness (n = 50, 68%), chills/rigors (n = 38,
51%), nausea (n = 45, 61%), diarrhea (n = 8, 11%), and abdominal pain (n = 13, 18%). The median fever clearance time was 53 hr (ränge 4 185) and was shorter than the parasite clearance time o f 65 hr (ränge 18-225). Clearance times were slightly longer i n those with P. f a l c i p a r u m infections (fever clearance time = 49 hr and parasite clearance time = 66 hr) compared with those with P. vivax infections (42 and 62.5 hr, respectively), but these differences were not statistically significant. In all patients, clinical Symptoms o f malaria disappeared and parasites could no longer be de-
tected on day 14 (Table 2). Subsequently, four infections recrudesced i n group 1 (treatment on day 0 only) on days 14, 22 (two patients), and 28, respectively, indicating that four (15.4%) o f 26 patients i n group 1 with P. f a l c i p a r u m infections recrudesced. In group 2 (treatment on days 0 and 7), none o f the 24 patients with P. f a l c i p a r u m malaria recrudesced. Although this difference was not statistically significant, a clinically relevant trend was apparent. The four patients whose infections recrudesced were white i n d i viduals; three o f them had used a chemoprophylactic (chloroquine), while the fourth patient had not used any chemoprophylactic. T h e i r body weights d i d not differ significantly from the successfully treated group, and their initial parasite counts were only slightly lower (3,500, 9,500, 10,500, and 48,000/jui, respectively). A l l four patients had returned from tropical Africa. A def-
3
HALOFANTRINE FOR MALARIA IN NONIMMUNE TRAVELERS
in her legs o n day 19 post-treatment. She was hospitalized a n d diagnosed as having G u i l l a i n Barre Syndrome (with typical cerebrospinal fluid findings) of unknown etiology. A 50-year-old man who reeeived halofantrine on days 0 a n d 7 developed viral encephalitis with disorientation and speech disturbance 23 days after initiating treatment. H e had a significant influenza A virus titer, indicating that influenza A virus was the probable cause o f his encephalitis. Both patients i m proved spontaneously.
TABLE 1
P a r a s i t e m i a i n the 74 m a l a r i a patients
i n this
Parasites/Ml
No. (%)
< 5,000 5,000-50,000 50,000-100,000 100,000-250,000 >250,000 Not done Total
9(12.2) 48 (64.9) 8(10.8) 2 (2.7) 3(4.1) 4 (5.4) 74(100.0)
study
inite eure o f these recrudescences was possible by treatment w i t h quinine or mefloquine. N o recrudescences were observed i n any patients i n both groups w i t h P . v i v a x malaria. C l i n i c a l tolerance to treatment with halofantrine was good, with only six patients reporting side effects. One patient each complained o f d i arrhea, itching, nausea, skin rash, fever, and angioneurotic (Quincke) edema. A l l reactions were graded as m i l d and disappeared spontaneously a few days after the end o f the halofantrine treatment. F i v e o f these six adverse reactions were confined to those w h o h a d a one-day therapy regimen. O n l y angioneurotic edema occurred i n a patient who reeeived two days o f therapy; concomitant to falciparum malaria, the same patient had Dengue fever. Treatment of this patient with a second dose o f halofantrine o n day 7 d i d not produce any adverse reaction. Therefore, it is more likely that the angioneurotic (Quincke) edem a was a reaction that occurred after the onset of Dengue fever. Thus, five (6.25%) of 80 patients developed m i l d , reversible side effects. H e m a tologic and clinical biochemical test results rem a i n e d within the normal limits after treatment in a l l patients. In addition, two patients developed neurologic Symptoms within the 28-day followup period that were judged to be unrelated to the intake o f halofantrine. A 32-year-old woman w h o reeeived halofantrine o n day 0 complained o f weakness
DISCUSSION
The role o f antimalarial drugs i n the control of malaria has undergone major revisions i n recent years with the increase o f drug resistance i n P l a s m o d i u m f a l c i p a r u m . T h i r t y years ago, the sensitivity o f the parasite was the n o r m . Today, resistance to chloroquine a n d other alternative Compounds is dominant and still spreading. T h i s has encouraged the development o f new drugs. The Walter Reed A r m y Institute of Research has identified various new antimalarial drugs, i n cluding halofantrine i n the 1970s. T h i s Compound, a phenanthrene methanol, proved to be more efficacious a n d less toxic than other new Compounds, and has undergone extensive evaluation since that t i m e . It has proved to be effective i n the treatment of drug-resistant strains of P . f a l c i p a r u m i n semi-immune patients i n various geographic l o c a l i t i e s . 1
16
16
1 7
1 8
8-13
In this study, we show that halofantrine is 100% effective i n the treatment o f malaria i n n o n i m mune patients i f a regimen including a second treatment o n day 7 is applied. A similar experience was reported by Bernard and others, who successfully treated 59 patients from tropical A f rica with a two-day course o f halofantrine o n days 1 a n d 8. T h e one-day dosing regimen (3 x 500 mg i n group 1) i n our study seems to be less effective, since four (15.4%) o f 26 patients with P . f a l c i p a r u m infections recrudesced. O u r results 14
TABLE 2
P a r a s i t e c l e a r a n c e a n d recovery
f r o m fever
i n the 74 m a l a r i a
patients
Day
No. (%) Median Parasite No. (%)
of parasitemic patients parasitemia (parasites//d) density/Ml (ränge) of patients with fever (>38°C)
Ö
2
5
7
\Ä~
74 (100) 40,350 50-500,000 71 (96)
56 (76) 2,000 50-20,000 25 (34)
2 (3) 0 < 50-2,250 3 (4)
1 (1) 0
