M. Haarbrink, 1 G. K. Abadi, 4 W. A. Buurman, 2 M. A. Dentener, 3 A. J. Terhell, 1 and M. Yazdanbakhsh 1

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1 564 Strong Association of Interleukin-6 and Lipopolysaccharide-Binding Protein with Severity of Adverse Reactions after Diethylcarbamazine Treatment of Microfilaremic Patients M. Haarbrink, 1 G. K. Abadi, 4 W. A. Buurman, 2 M. A. Dentener, 3 A. J. Terhell, 1 and M. Yazdanbakhsh 1 1 Department of Parasitology, Leiden University Medical Center, Leiden, and Departments of 2 Surgery and 3 Pulmonology, Maastricht University, Maastricht, The Netherlands; 4 Department of Parasitology, Hasanuddin University, Ujung Pandang, Indonesia To assess the involvement of inflammatory mediators in the development of adverse reactions in filarial patients undergoing treatment, 29 microfilaremic subjects were treated with diethylcarbamazine (DEC). Before and at serial time points after initiation of treatment, plasma levels of inflammatory mediators and DEC were measured, and adverse reactions were recorded. Patients experienced no or mild, moderate, or severe adverse reactions. Increasing pretreatment microfilarial counts were associated with escalating severity of adverse reactions. Plasma concentrations of DEC were not different among patients suffering from varying degrees of illness. Interleukin (IL) 6, IL-10, lipopolysaccharide-binding protein (LBP), and soluble tumor necrosis factor receptors (stnf-rs) increased after treatment. IL-6 and LBP, however, showed the strongest association with adverse reactions. Increasing levels of these molecules were closely correlated with the mounting severity of adverse reactions, which raises the possibility that they play an important role in systemic inflammation that arises after DEC treatment of filarial patients. Human lymphatic filariasis caused by nematode parasites of Brugia malayi and Wuchereria bancrofti is a major cause of morbidity in tropical countries. Many control programs have been implemented to reduce the transmission of filarial infection by treating the host with antifilarial drugs to decrease microfilaremia. The drug of choice for the treatment of lymphatic filariasis is diethylcarbamazine citrate (DEC), which is an excellent microfilaricide with considerable macrofilaricidal properties [1 3]. Treatment with DEC, however, can result in severe inflammatory-like adverse reactions resulting in decreased patient compliance. The reactions include fever, headache, and myalgia [4] and resemble those seen during acute systemic inflammatory responses caused by bacterial infections [5] and during treatment with anti-cd3 antibodies [6]. These adverse reactions Received 24 November 1999; revised 20 April 2000; electronically published 28 July This study was carried out in collaboration with the University of Hasanuddin and has received the approval of the Commission of Medical Ethics, Faculty of Medicine, Hasanuddin University. Informed consent was obtained from all patients before clinical and parasitological study and blood withdrawal, in accordance with the guidelines of the Indonesian Department of Health and Human Services. Financial support: the Scientific Directorate of the Commission of the European Communities under the Science and Technology for Development Programme INCO-DC (ERBIC-18CT970245). Reprints or correspondence: Dr. Maria Yazdanbakhsh, Dept. of Parasitology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands (M.Yazdanbakhsh@lumc.nl). The Journal of Infectious Diseases 2000;182: by the Infectious Diseases Society of America. All rights reserved /2000/ $02.00 have been attributed to the release of inflammatory mediators such as tumor necrosis factor (TNF) a, interleukin (IL) 1, IL- 2, IL-6, IL-8, and interferon (IFN) g, as well as complement activation. Indeed, adverse reactions to DEC are also thought to be a result of proinflammatory responses to antigens released from killed microfilariae rather than a direct drug or metabolite toxicity [2]. In order to curtail adverse responses without compromising drug effectiveness, it is essential to dissect the immunologic mechanisms mediating these reactions after DEC treatment of filarial patients. Such knowledge will also benefit the recent initiatives from the World Health Organization to implement new strategies and tools for the control of lymphatic filariasis [7]. There are indications that TNF-a and/or IL-6 increase within 24 h after DEC treatment in lymphatic filariasis patients [8, 9]. These results led us to conduct a study in which we investigated this in more detail. In addition to the classic inflammatory compounds such as IL-6, IL-8, and TNF and its receptors, we also included lipopolysaccharide-binding protein (LBP) and IL- 10 in our measurements. LBP is a member of a growing family of acute-phase proteins synthesized by hepatocytes in response to early cytokines such as IL-1 and IL-6, and it takes part in the inflammatory cascade involved in febrile illness [10]. The inclusion of IL-10 in our study was prompted by the mounting evidence for the role this cytokine plays in restricting proinflammatory responses during infectious and febrile diseases [11, 12]. Because an inflammation is a result of a delicate balance between pro- and anti-inflammatory processes, we set out to study in 29 microfilaremic individuals the levels of TNF-a, IL- 6, IL-8, IL-10, LBP, soluble TNF receptor (stnf) R55, and

2 JID 2000;182 (August) IL-6 and LBP in Treatment of Microfilaremia 565 stnf-r75 and assessed their association with adverse reactions after treatment with DEC. The data show a clear correlation between inflammatory mediators and the severity of adverse reactions. Increased levels of IL-6, IL-10, LBP, and stnf-rs were correlated with severe systemic reactions after DEC treatment of filarial patients. Materials and Methods Table 1. Numbers of study subjects, pretreatment microfilarial counts, and antifilarial IgG4 levels in patients experiencing different categories of adverse reactions. Adverse reaction No. (%) of subjects mf/10 ml Antifilarial IgG4 (AU) No or mild 18 (62.1) 74 (28 197) 542,750 (330, ,046) Moderate 7 (24.1) 1268 a ( ) 590,065 (284,577 1,224,334) Severe 4 (13.8) 3060 b (342 27,353) 254,449 (66, ,039) Total 29 (100) 235 ( ) 498,884 (348, ,167) NOTE. Data are given as geometric means (95% confidence interval of the mean), unless otherwise indicated. AU, arbitrary units; mf, microfilariae. a Significantly different from individuals with no or mild adverse reactions ( P p.003; t test). b Significantly different from individuals with no or mild adverse reactions ( P p.0019; t test). Study population. In the B. malayi endemic area of Karondang, in Sulawesi, Indonesia, where the microfilaria prevalence was 33.3%, the inhabitants were informed of the purpose of the study, and volunteers were registered. Individuals were enrolled in the study if they had given informed consent and were eligible for DEC treatment if they were microfilaria (mf) positive. Pregnant women and individuals with proteinuria were excluded from the study. Twenty-nine mf-positive individuals (range mf/10 ml) were included in the study. Study participants consisted of 19 males (median age 35 years; range years) and 10 females (median age 35 years; range years). Study design. All mf-positive individuals were admitted to the local health center for 5 consecutive days, after which most adverse reactions had subsided and treatment could be continued at home. Each study subject was treated for 12 consecutive days with an oral dose of 6 mg/kg body weight DEC. The DEC was administered at 8:00 AM after a standard breakfast. Tablets were swallowed under supervision. Before DEC intake and at serial time points of 2, 4, 8, 24, 32, 48, and 120 h after the first dose of DEC at day 1, 10 ml venous blood was drawn, and body temperature (in the armpit for 15 min), heart rate, and blood pressure were registered. In parallel, at the same serial time points, individuals were physically examined, with particular attention for swollen inguinal lymph nodes and edema in extremities. These clinical findings and complaints such as arthralgia, dizziness, headache, inguinal lymphnode enlargement, myalgia, and fever were registered as either present or absent and quantified following an arbitrary system as published elsewhere [13]. In brief, 0 points were given for the absence of symptoms and body temperatures!37.7 C, 1 point for the presence of arthralgia, dizziness, lymph-node enlargement or myalgia, and 2 points for headache. Body temperatures ranging from 37.7 C to 38.5 C were assigned 5 points, and temperatures C were assigned 10 points. Depending on the total individual reaction scores, adverse reactions were classified into 3 categories: no or mild, with 0 14 points, moderate, with points, and severe, with 25 points (table 1). Collection of blood samples. To evaluate the presence of microfilariae before DEC treatment, it was essential to collect blood samples at night, because B. malayi mf show a nocturnal periodicity in this region. A 10-mL night blood sample (taken between 21:30 and 24:00 PM) was collected into EDTA-containing tubes (final concentration of 0.05 M). The blood was centrifuged at 1500 g for 10 min. Plasma samples were stored immediately after separation at 20 C for several months and subsequently transported to the Netherlands on dry ice, where they were stored at 70 C until use. The remaining red blood cells were filtered as described in the following section. Blood samples for immunologic and DEC measurements were also taken at the time points 2, 4, 8, 24, 32, 48, and 120 h after treatment. Parasitological examination. Venous night blood samples taken before treatment were centrifuged to remove and store plasma. To the remaining red blood cells, 10 ml distilled water was added, shaken, and filtered the next day through a Millipore membrane with a pore size of 5 mm. The filters were air-dried, fixed with methanol, stained with Giemsa, and examined with a light microscope for the presence of mf. Levels of inflammatory mediators. Cytokine ELISA for IL-6, IL-8, IL-10, TNF-a, stnf-r55, stnf-r75, and LBP were performed on EDTA plasma samples taken before and at 2, 4, 8, 24, 32, 48, and 120 h after initiation of DEC treatment. Commercial kits were used to measure IL-6, IL-8, IL-10, and TNF-a (CLB, Amsterdam), with detection limits of 0.6, 1, 1.2, and 1.4 pg/ml, respectively. stnf-r55 and stnf-r75 were detected as described elsewhere [14]. The detection limit of both assays was 100 pg/ml. LBP was determined by an ELISA, as described elsewhere [15]. The detection limit for the LBP assay was 200 pg/ml. Levels of specific IgG4. Antifilarial IgG4 antibodies were determined in all pretreatment plasma samples by ELISA, as described elsewhere [13]. The antifilarial IgG4 levels were expressed as arbitrary units/ml (AU/mL) by extrapolation from a standard curve of a positive control plasma containing AU/mL parasite-specific IgG4. Concentrations of DEC. DEC concentrations were determined in plasma samples obtained at 2, 4, 8, 24, 32, 48, and 120 h after initiation of treatment by competitive ELISA, as described by Mitsui et al. [16]. In brief, plasma samples were simultaneously incubated with mouse anti-dec antiserum over a DEC-poly-Llysine solid phase. The binding of anti-dec antiserum was subsequently detected by using sheep anti mouse IgG peroxidase conjugate as a tracer. The detection limit of the ELISA was 1 ng/ml of DEC. Statistical analysis. Because the levels of all inflammatory mediators, antifilarial IgG4 levels, and microfilarial counts approximated a normal distribution after 10 log-transformation, log 10 (cytokine), log 10 (IgG4) levels, and log 10 (mf 1) were used for analysis of the data. Mean levels of inflammatory mediators, IgG4 levels, and microfilarial counts were calculated as the geometric mean (GM) and its 95% confidence interval (95% CI). The GM of the peak values of inflammatory mediators per group was calculated using the highest value for each patient. The t test with Bonferoni

3 566 Haarbrink et al. JID 2000;182 (August) significantly different between the groups with differing severity of adverse reactions ( P p.3). Levels of IL-6 after DEC treatment. Pretreatment levels of IL-6, a major regulator of the acute-phase response, were not significantly different across the 3 groups experiencing varying degrees of adverse reactions. At 2 and 4 h after DEC treatment, levels of IL-6 started to increase in all individuals with moderate and severe adverse reactions and were highest in blood samples taken at 8 or 24 h after treatment (figure 1). Peak levels of IL- 6 increased with severity of adverse reactions, being significantly higher in patients with either severe ( P!.0001) or moderate ( P p.001) adverse reactions than in those with no or mild reactions. Furthermore, IL-6 levels correlated significantly with body temperature ( r p 0.58; P!.0001; data not shown). Levels of LBP after DEC treatment. Pretreatment levels of acute-phase protein LBP were not significantly different across the 3 groups with varying degrees of adverse reactions (figure Figure 1. Interleukin (IL) 6 plasma levels after diethylcarbamazine citrate treatment in individuals with no or mild, moderate, or severe adverse reactions. Each line represents 1 individual. The graph at the bottom summarizes the results by showing the geometric means of IL- 6 levels for each clinical group. correction was used to compare GMs of inflammatory mediator peak levels, antifilarial IgG4, or microfilarial counts between 2 groups. The analysis of variance (ANOVA) was used for comparisons across 3 groups of adverse reactions. Pearson s correlation test was used to calculate concordance between data sets. Results Pretreatment microfilarial densities and antifilarial IgG4 levels. A total of 29 mf-positive individuals were included in this study. Pretreatment microfilarial densities and antifilarial IgG4 levels of individuals experiencing different degrees of adverse reactions are summarized in table 1. The most prominent adverse reactions after DEC intake were fever, headache, and myalgia. Individuals with no or mild adverse reactions had significantly lower pretreatment microfilarial counts than did those suffering from moderate or severe reactions (P p.003 and P p.0019, respectively). Furthermore, elevated levels of antifilarial IgG4 indicating active infection [17, 18] were not Figure 2. Lipopolysaccharide-binding protein (LBP) plasma levels after diethylcarbamazine citrate treatment in individuals with no or mild, moderate, or severe adverse reactions. Each line represents 1 individual. The graph at the bottom summarizes the results by showing the geometric means of LBP levels for each clinical group.

4 JID 2000;182 (August) IL-6 and LBP in Treatment of Microfilaremia 567 2). Posttreatment LBP levels of all individuals with moderate and severe reactions started to increase at 8 h, reaching peak levels at h, and remained elevated until day 5 of treatment. The peak LBP levels of the severe and the moderate group were higher than the levels measured in the no/mild group ( P p.066 and P p.007, respectively). Like IL-6, levels of LBP correlated significantly with body temperature ( r p 0.30, P!.0001; data not shown). Levels of IL-8 after DEC treatment. Pretreatment levels of IL-8 in the no/mild (15.8 pg/ml), moderate (20.2 pg/ml), and severe adverse reaction groups (16.4 pg/ml) were not significantly different. IL-8 levels were slightly elevated in a few of the study subjects at 24 and 32 h after treatment, but this did not reach statistical significance, compared with pretreatment values (data not shown). Levels of TNF-a, stnf-r75, and R55 after DEC treatment. The detection limit of our TNF-a assay was 1.4 pg/ml. Negligible levels (!5 pg/ml) of TNF-a were detected in samples tested, with the exception of 2 patients with no/mild symptoms for whom TNF-a was measurable at a single time point (13.2 pg/ml at 8 h for one and pg/ml at 32 h after treatment for another). Two types of TNF receptor, TNF-R55 and TNF- R75, have been characterized and are shed from the cell membrane on activation [19]. Because these molecules are thought to play an important anti-inflammatory role by neutralizing TNF, we measured systemic concentrations of both receptors. At 8 h after treatment, stnf-r75 started to rise, reaching maximal levels after 24 h. The peak stnf-r75 levels were significantly higher in individuals with moderate adverse reactions (geometric mean pg/ml, 95% CI , P p.043), compared with individuals with no or mild adverse reactions ( pg/ml, ). Although in the group suffering from severe adverse reactions the stnf- R75 levels showed a clear peak (2135 pg/ml, ) that was higher than the peak in the no/mild group, the difference was not statistically significant ( P p.163). The levels of stnf-r55 ( pg/ml, ) were, however, significantly higher ( P!.001) in the group with severe adverse reactions than in those experiencing moderate (782.9 pg/ml, ) or no/mild (722.6 pg/ml, ) reactions. In most individuals, the levels of stnf-r55 and -R75 remained elevated until 5 days after initiation of treatment. Levels of IL-10 after DEC treatment. Pretreatment levels of the anti-inflammatory cytokine IL-10 were not significantly different across the 3 groups of adverse reactions. Between 2 and 8 h after DEC intake, IL-10 levels started to increase in 3 of 4 individuals who suffered from severe adverse reactions and in 3 of 7 who experienced moderate reactions (figure 3). In one patient who did not experience any adverse reaction, high levels of IL-10 were measured with a peak at 4 h after treatment. This patient (depicted in the figure as an open triangle in the no/mild group) also showed elevated IL-6 (38.4 pg/ml, at 24 h) and LBP (92 mg/ml, at 48 h), which indicates some level of Figure 3. Interleukin (IL) 10 plasma levels after diethylcarbamazine citrate treatment in individuals with no or mild, moderate, or severe adverse reactions. Each line represents 1 individual. The graph at the bottom summarizes the results by showing the geometric means of IL- 10 levels for each clinical group. immune activation as a result of mf clearance, which was clinically asymptomatic. The peak IL-10 levels in individuals with severe reactions were significantly higher ( P p.001) than in individuals suffering from no or mild reactions. Plasma DEC concentrations in subjects with varying degrees of adverse reactions. The concentration of DEC in plasma was determined for each patient (figure 4). DEC concentrations could not explain the varying degrees of adverse reactions experienced by patients. The area under the DEC concentration/ time curve were not significantly different between the no and mild (4.75 mg/ml), moderate (5.64 mg/ml), and severe (5.52 mg/ml) adverse reaction groups ( P p.520). Discussion The severity of adverse reactions after DEC treatment correlated with pretreatment mf counts, confirming results elsewhere in lymphatic filariasis and onchocerciasis [20, 21]. The

5 568 Haarbrink et al. JID 2000;182 (August) Figure 4. Plasma concentrations of diethylcarbamazine citrate (DEC) in individuals with no or mild, moderate, or severe adverse reactions. Each line represents 1 individual. The graph at the bottom summarizes the results by showing the average concentrations of DEC for each clinical group. concurrent measurement of DEC and inflammatory mediators in our patients showed that DEC concentrations could not explain the differences in adverse reactions but that peak levels of proinflammatory cytokines increased with severity of adverse reactions. Detailed kinetic studies showed the strongest association between IL-6 and LBP with severity of adverse reactions. We found that IL-6 started to rise as early as 2 4 h, reaching maximal levels 8 h after treatment; this finding was concurrent with fever, which rose between 4 and 8 h after treatment, as elsewhere reported in detail [13]. The correlation between IL- 6 and body temperature has been reported in other filariasis studies [8, 9] and agrees with the pyrogenic activity of IL-6 [22]. Circulating IL-6 is also known to play a central role in the induction of acute-phase proteins that are involved in inflammatory reactions [23]. We found that levels of acute-phase protein, LBP, started to rise after IL-6, at 8 h, and also peaked later than IL-6, between 24 and 48 h after DEC treatment. Compared with pretreatment levels, LBP remained elevated in all individuals with moderate and severe adverse reactions up to day 5 after initiation of treatment, indicating an ongoing inflammation. It has recently been shown that LBP is also able to bind phospholipids [24]. It is therefore possible to envisage a role for LBP in adverse reactions recorded here, by its ability to act as a shuttle for insoluble lipids released from degenerating microfilariae. Some of these complexes can then be recognized by receptors, resulting in cellular activation and onset of an immunologic cascade of inflammation that may have evolved to combat invading pathogens. In agreement with some reports [9, 25], but in contrast to studies of Turner et al. [8], we could not detect TNF-a in plasma samples of drug-treated filarial patients suffering from systemic inflammation. The absence of TNF-a in our patients undergoing DEC treatment could imply that the adverse reactions after DEC treatment are less severe than symptoms seen in infections where TNF-a is elevated. It is possible that TNF-a is not detectable in our study samples because of either degradation or wrong sampling times. It should also be noted that the levels of stnf receptors measured in our samples are not high enough to inhibit the detection of circulating TNF. Within the inflammatory process, a delicate balance exists between the potential to clear an infection and the potential to inflict tissue injury. Thus, inflammatory stimuli also activate the production of specific cytokines neutralizing molecules such as soluble TNF receptors and counterinflammatory cytokines such as IL-10. We observed that blood levels of stnf-rs and IL-10 were elevated in those suffering from severe adverse reactions. Moreover, a clear positive correlation between IL-6 and IL-10 concentrations (not shown) supports the notion that proinflammatory responses induce the production of anti-inflammatory cytokines. Adverse reactions after DEC therapy resemble those seen after experimental administration of LPS or after injection of anti-cd3 antibodies as a prophylaxis for acute rejection after organ grafting [26]. The former involves monocyte/macrophage activation, whereas the latter treatment causes immune activation that is mediated via T cells. The release of antigens from damaged mf could potentially activate the inflammatory processes via both the monocyte/macrophage or the T cell stimulation route. It has recently been reported that filarial parasites contain Wolbachia as an endosymbiotic bacteria [27 29]. This opens the possibility that destruction of mf after DEC treatment leads to the release of these bacteria and their products that in turn may initiate a systemic inflammatory response. Detection of Wolbachia DNA in our plasma samples by means of the polymerase chain reaction [30] is currently under investigation. In conclusion, the findings reported here support the notion that increasing adverse reactions after DEC treatment may be

6 JID 2000;182 (August) IL-6 and LBP in Treatment of Microfilaremia 569 the result of an exaggerated host inflammatory response stimulated by high antigen load released from killed or degenerating mf [2]. The reactions to DEC may be mediated by inflammatory molecules such as IL-6 and LBP that are in turn kept in check by anti-inflammatory processes regulated by IL-10 and stnf- R. These data can now be taken into consideration when seeking new chemotherapeutic measures. Acknowledgments We thank the patients who took part in this study and the support of the staff at the Pusat Kesehatan Masyarakat Hospital in Babana, Indonesia. We gratefully acknowledge the assistance in Indonesia of Abdul Jalil, Abdul Rashid, Sidra, Jolanda Gelderblom, Esther de Jager, Ellen Peters, Jan Willem Koot, and Anita van den Biggelaar, as well as Mrs. Christin and Mrs. Hasni. We also thank Dr. Mustafa, Dr. Asri, and Eddy Sanneng, of Communicable Disease Control in Ujung Pandang, for their cooperation and help in organizing field trips; Dr. Y. Mitsui, for measuring diethylcarbamazine citrate concentrations in plasma samples; and KLM (Royal Dutch Airlines), for sponsoring the transport of patient material. References 1. Ch en TT. Demonstration of macrofilaricidal action of Hetrazan, antimony and arsenic preparations in man. Chin Med J 1964;2: Ottesen EA. Efficacy of diethylcarbamazine in eradicating infection with lymphatic dwelling filariae in humans. Rev Infect Dis 1985;7: Ottesen EA, Ramachandran CP. Lymphatic filariasis infection and disease: control strategies. Parasitol Today 1995;11: Maizels RM, Denham DA. Diethylcarbamazine (DEC): immunopharmacological interactions of an anti-filarial drug. Parasitology 1992;105:S49 S Blackwell TS, Christman JW. Sepsis and cytokines: current status. Br J Anaesth 1996;77: Abramowicz D, Schandene L, Goldman M, et al. Release of tumor necrosis factor, interleukin-2 and gamma interferon in serum after injection of OKT3 monoclonal antibody in kidney transplant recipients. Transplantation 1989;47: Ottesen EA, Duke BOL, Karam M, Behbehani K. Strategies and tools for the control/elimination of lymphatic filariasis. Bull World Health Organ 1997;75: Turner PF, Rockett KA, Ottesen EA, et al. Interleukin-6 and tumor necrosis factor in the pathogenesis of adverse reactions after treatment of lymphatic filariasis and onchocerciasis. J Infect Dis 1994;169: Yazdanbakhsh M, Duym L, Aarden L, Partono F. Serum interleukin-6 levels and adverse reactions to diethylcarbamazine in lymphatic filariasis. J Infect Dis 1992;166: Grube BJ, Cochane CG, Ye RD, et al. Lipopolysaccharide binding protein expression in primary human hepatocytes and HepG2 hepatoma cells. J Biol Chem 1994;269: Glynn P, Coakley R, Kilgallen I, Murphy N, O Neill S. Circulating interleukin 6 and interleukin 10 in community acquired pneumonia. Thorax 1999;54: Van Dissel JT, van Langevelde P, Westendorp RG, Kwappenberg K, Frolich M. Anti-inflammatory cytokine profile and mortality in febrile patients. Lancet 1998;351: Haarbrink M, Terhell AJ, Abadi GK, Mitsui Y, Yazdanbakhsh M. Adverse reactions following diethylcarbamazine (DEC) intake in endemic normals, microfilaraemics and elephantiasis patients. Trans R Soc Trop Med Hyg 1999;93: Leeuwenberg JFM, Dentener MA, Buurman WA. Lipopolysaccharide LPSmediated soluble TNF receptor release and TNF receptor expression by monocytes; role of CD14, LPS binding protein and bactericidal/permeability-increasing protein. J Immunol 1994;152: Froon AHM, Dentener MA, Greve JWM, Ramsay G, Buurman WA. LPS toxicity regulating proteins in bacteremia. J Infect Dis 1995;171: Mitsui Y, Takamura N, Fujimaki Y, et al. Development of a competitive enzyme-linked immunosorbent assay for diethylcarbamazine. Trop Med Int Health 1996;1: Wamae CN, Roberts JM, Eberhard ML, Lammie PJ. Kinetics of circulating human IgG4 after diethylcarbamazine and ivermectin treatment of bancroftian filariasis. J Infect Dis 1992;165: Kurniawan Atmadja A, Atkinson R, Sartono E, Partono F, Yazdanbakhsh M. Differential decline in filarial specific IgG1, IgG4 and IgE antibodies following diethylcarbamazine chemotherapy of Brugia malayi infected patients. J Infect Dis 1995;172: Porteu F, Nathan CF. Shedding of tumour necrosis factor receptors by activated human neutrophils. J Exp Med 1990;172: Partono F, Purnomo, Oemijati S, Soewarta A. The long-term effects of repeated diethylcarbamazine administration with special reference to microfilaraemia and elephantiasis. Acta Tropica 1981;38: Francis H, Awadzi K, Ottesen EA. The mazzotti reaction following treatment of onchocerciasis with diethylcarbamazine: clinical severity as a function of infection intensity. Am J Trop Med Hyg 1985;34: Helle M, Brakenhoff JPJ, de Groot ER, Aarden LA. Interleukin 6 is involved in interleukin 1-induced activities. Eur J Immunol 1988;18: Baumann H, Gauldie J. The acute phase response. Immunol Today 1994; 15: Yu B, Hailman E, Wright SD. Lipopolysaccharide binding protein and soluble CD14 catalyze exchange of phospholipids. J Clin Invest 1997;99: Njoo FL, Hack CE, Oosting J, et al. C-reactive protein and interleukin-6 are elevated in onchocerciasis patients after ivermectin treatment. J Infect Dis 1994;170: Parlevliet KJ, Bemelman FJ, Yong SL, et al. Toxicity of OKT# increase with dosage: a controlled study in renal transplant recipients. Transpl Int 1995; 8: McLaren DJ, Worms MJ, Laurence BR, Simpson MG. Micro-organisms in filarial larvae (Nematoda). Trans R Soc Trop Med Hyg 1975;69: Hoerauf A, Nissen-Pähle K, Schmetz C, et al. Tetracycline therapy targets intracellular bacteria in the filarial nematode Litomosoides sigmodontis and results in filarial infertility. J Clin Invest 1999;103: Taylor MJ, Cross HF, Bilo K. Inflammatory responses induced by the filarial nematode Brugia malayi are mediated by Lipopolysaccharide-like activity from endosymbiotic Wolbachia bacteria. J Exp Med 2000;191: Sironi M, Bandi C, Sacchi L, et al. Molecular evidence for a close relative of the arthropod symbiont Wolbachia in a filarial worm. Mol Biochem Parasitol 1995;74:223 7.

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