TRANSACTIONS OFTHEROYALSOCIETY OFTROPICAL MEDICINE ANDHYGIENE (1992)
Diethylcarbamazine in the control of splenomegaly filariasis in the Ok Tedi area of Papua New Guinea
531
86, 531-536
associated
with Bancroftian
Gerrit J. Schuurkampl, Richard K. Kereu l, Peter K. Bulungol’, Aigol Kawerengl, William H. Poponl, Greg G. Crane2, Judy Greenidge2 and Paul E. Spicer 1 ‘Medical Department, Ok Tedi Mining Limited, P.O. Box I, Tabubil, Western Province, Papua New Guinea; 2Haematolog_yDepartment, Repatriation General Hospital Concord, Concord, New South Wales 2139, Australia Abstract
Bancroftian lilariasis is highly endemic in the Ok Tedi region of Papua New Guinea, with a reported mean rate of 39% before the implementation of a single-dose diethylcarbamazine (DEC) treatment programme in 1986. This was followed bv a 72% decline in the rate of detectable microfilaraemia and a 40% reduction in pre- and post-treatment spienomegaly. No significant difference was observedwhen spleen enlargement was compared to the presenceof patent malaria. A significant difference in splenomegaly was observed between DEC-treated villagers and their untreated counterparts. Significant differences were reported in the rate of detectable microfilariae of Wuchereria bancroft!, but not of malaria, between the 2 groups. The number of DEC administrations and the period of time smce the first treatment played a significant role immunologicallv. Sienificant differences were observed in immunoalobulin (Ia) M and IaG levels and in the extent of splenom~galy between DEC-treated and untreated areas. Fi1aria.linfection associatedwith malaria resulted in higher spleen rates and size. W. bancrofti is a major contributor to splenomegaly in the Ok Tedi region, and sulenomenalv associatedwith bancroftian lilariasis can be reduced or controlled by low, well-spaced dosesbf DEC.” . Introduction
Malaria is considered to be the principle cause of illhealth in the Ok Tedi region of Western province, Papua New Guinea, and is assumed to be responsible for high rates of splenomegaly and hepatomegaly (TAUKURO& NURSE, 1979a, 1979b). The hiah rate of filariasis (34%) due to ‘Wuche&ia bancrofti reported by CATTANIkt al: f 1983) for the Star Mountains (immediate Ok Tedi area) was sunnorted bv the 13% incidence of microtilaraemia detected in daytime blood smearsfrom villagers around Atemkit. 1000 m above sea level. 5 vears earlier (TAUKURO et’al., 1980). The high rate of “daytime microfilaraemia (11.3%) observed amongst local employeesof Ok Tedi- Mining Limited during routine passive casedetection for malaria in 1982, a time of intense local recruitment from all parts of the Ok Tedi region, were consistent with the above reports (SCHUURKAMP et aZ., 1987a). A review in 1986 of the Wopkaimin population, the major linguistic group within the immediate Ok Tedi area, showed major declines in hepatomegaly, splenomegaly, enlarged lymph nodes, and malaria amongst others since 1982 (LOURIE, 1987). Overall, 16% had some degree of liver enlargement (LOURIE, 1987) compared to 77% during the 1982-1983baseline (CATTANI et al., 1983), and the prevalence of enlarged livers was reduced from 33% to 3%. This corresponded with a reduction in the prevalence of enlarged spleens in children under 10 years of age from the baseline level of 72.8% to 28.5% in 1986. Larger spleens were less frequently seen (16% of the whole sample had spleensof Hackett’s grade III or larger on follow-up). In general, the splenomegaly rate was reduced from 76.1% to 39.7% in 4 years. The reduction in averageenlarged spleen (AES) size (2.32 to 1.22) was highly significant. Rates of splenomegaly in adults varied with altitude: 80-90% for those living in the 610-765 m range above sea level and 68% at 1400 m (LOURIE, 1987). The findings of the Ok Tedi Health and Nutrition Project (LOURIE, 1987) were consistent with a reduced malarial load in the population due to malaria control activities implemented by Ok Tedi Mining Limited (SCHUURKAMP et al., 1987a, 198713). Filariasis is also highly endemic amongst the Ningerum alone the southern frinee of the Ok Tedi area. In 1978 a 47% rate of microfilariemia was reported amongst the north Ningerum in the 400-600 m range above sea level, and 28% in the foothills below (TAUKUROet al., 1980). Addressfor correspondence: Dr Gerrit Schuurkamp,Medical Department,Ok Tedi Mining Limited, P.O. Box 1, Tabubil, WesternProvince,PapuaNew Guinea.
It has been suggestedthat a substantial proportion of the acute febrile episodes reported by aid post orderlies in the areais due to filariasis. Inguinal lymphadenopathy was widespread throughout the population, presumably associatedwith leg sepsis,but in somecasesit was almost certainly a consequence of tilariasis. Despite the high rates of lilariasis in the region, the clinical manifestation of chronic illness (elephantiasis) was rare compared to that in non-Ningerum speaking villages along the Fly river south of Kiunga (TAUKURO& NURSE,1979b). TAUKURO et al. (1980) noted a ‘puzzling’ higher spleen rate (51%) in the Atemkit area of the Star Mountains, Papua New Guinea, amongst 104 villagers 10 years of age and older, despite a low rate of malaria parasitaemia (13%). Children under 10 years of age, on the other hand, demonstrated a higher malaria parasite rate (56%) and a somewhat lower spleen rate (44%). A decadelater the situation was unchanned at Atemkit in the over 10 years age group, with a spleen rate of 93% (39/42), a persistent low erade AES size of 2.1. and a 12% malaria parasite rate” (SCHUURKAMPet al.,’ 1990). Microtilariae (mf) were detected in 29% of these individuals, with the highest mean microfilaraemia recorded for the area, 138mf/20 ul. During the 1988 malariaifilariometric surveys of the Ok Tedi coveragearea (3000 km2) identical low malaria parasite rates (14%) were found’ both in populations treated with diethvlcarbamazine IDEC) and in untreated populations, but ihe spleen rates were dissimilar (47% and 76% respectively) (SCHUURKAMP et aE., 1990). The ‘puzzling’ high spleen rate associated with low malaria parasitaemia in older individuals was observed as recently as 1990 in 27 Kawentinkin villagers not receiving DEC at Atemkit. These villagers demonstrated rates similar to those reported in 1978 for the same general area: 56% splenomegaly, 15%malaria and 82% microfilaraemic, compared to rates of 47% (35/75) splenomegaly, 7% (5/75) malaria and 19% (14/75) microfilaria in villagers in the samecommunitv treated with DEC annuallv since 1988. Hepatomegaly is strongly associated with splenomegaly in the Star Mountains of Western province, unlike the Middle Flv region directlv to the south (TAUKURO et al., 19gO; ~CATTANI et al., 1983).\ The microfilaricidal action of DEC depends upon the proper function of the humoral and cellular immune mechanism of the host. Most of the mf in the blood are destroyed by the reticuloendothelial cells of the liver (WHO, 1984). Information is lacking concerning the association of immunological changes and splenomegaly in humans with
532 filariasis. Splenic hyperplasia and antigen-reactive spleen cells have been reported in jirds sometime after infection with Diataelonema viteae (ABRAHAMet al.. 1986). Snlenic suppre&ion of microfilaraemia has been demonstrated in almost every primate species infected with Loa, Brugia and Mansonella, and most reports deal with mf sequestering or being filtered from the blood bv the soleen, causiig gross morphological changesor abnormal&es of the spleen (ORIHEL& EBERHARD,1985). Three postulates were proposed in 1988 for investigation for the Ok Tedi area: (i) that splenomegalyin the Ok Tedi area, where chronic tilariasis is known to exist, is not due to malaria alone; (ii) that splenomegaly would most probably persist or be enhanced by filarial infection; and (iii) that DEC might be effective in the control of splenomegaly. Materials and Methods Field procedures
Treatment with diethylcarbamazine citrate (DEC), in 50 mg tablet form, commenced in June 1986. A dose of 6 mg per kg body weight was given as a single dose at semi-annual intervals during the initial 2-year phase 1 introductory programme involving 5 villages (group 1) (SCHUURKAMP et al., 1990). The successful phase 1 programme was expanded into an annual single-doseadministration of DEC over a larger area comprising an additional 7 villages (group 2>. Drugging-commenced at 20:O0. after villagers had eaten sufficient to tolerate drug. ingestion and as&re maximum efficiency of the drug on active circulating parasites. Individuals under 15 kg body weight, pregnant femalesand the ill were excluded. The occasional side-effects often associated with DEC and the release of foreign protein into the blood from dead mf were subdued by administering an antihistamine with DEC treatment during the first 2 drug cycles. Injectable cortisone and oxygen were available in case of hypersensitivity or anaphylactic shock. Villagers were monitored for 24-48 h after treatment. Grotto 3 consisted of other inhabitants (immigrants or tempoiary visitors) of the 12 survey villages, who had received at least one DEC treatment since 1986. Filariolmalariometric
Antigen and antibody were allowed to react for 6 min and the amount of light scatteredwas measuredand compared to a standard calibration curve constructed weekly, using Behring standard sera. Internal (serum) controls were included with each run. and a standard Pamta New Guinea serum pool of known Ig concentration was included in selectedruns. Test samples were run in batches of 32; 200 1 were reauired for each test. When the initial results ! ell outside the range of the calibration curve, appropriate dilution was carried out by the instrument. All results, expressed in mg/dl, were converted to loglo values before statistical analysis, since Ig values approximate to a log normal distribution. Statistical analysis
All information from field and laboratory surveys was entered into a computer database(Borland-Ansa’s Paradox@, version 3.5) and retrieved information assessed statistically with the aid of Statistical Analysis Systems@ software version 5.18 (SAS Institute Inc.) on a Data General network MV@ computer. Fisher’s exact test and x2 were used to test differences in proportions and determine significance levels. x2, degreesof freedom (df) and probability (P) values are reported for each observation. Assessment of serological data was based on log data evaluations by analysis of variance (ANOVA) -using Tukey’s studentized range (HSD) test for the 4 variables IgA, IgM, IgG and spleen enlargement. Results Malaria and filariasis compared with splenomegaly before and after treatment
Table 1 summarizes observations in the 12 villages involved in the DEC treatment programme. A significant improvement was seen after treatment in villagers with and without splenomegaly when assessed for the presence of detectable microfilaraemia (x*=42.192 for 1 df; P
Diethylcarbamazine in the control of splenomegaly filariasis in the Ok Tedi area of Papua New Guinea
531
86, 531-536
associated
with Bancroftian
Gerrit J. Schuurkampl, Richard K. Kereu l, Peter K. Bulungol’, Aigol Kawerengl, William H. Poponl, Greg G. Crane2, Judy Greenidge2 and Paul E. Spicer 1 ‘Medical Department, Ok Tedi Mining Limited, P.O. Box I, Tabubil, Western Province, Papua New Guinea; 2Haematolog_yDepartment, Repatriation General Hospital Concord, Concord, New South Wales 2139, Australia Abstract
Bancroftian lilariasis is highly endemic in the Ok Tedi region of Papua New Guinea, with a reported mean rate of 39% before the implementation of a single-dose diethylcarbamazine (DEC) treatment programme in 1986. This was followed bv a 72% decline in the rate of detectable microfilaraemia and a 40% reduction in pre- and post-treatment spienomegaly. No significant difference was observedwhen spleen enlargement was compared to the presenceof patent malaria. A significant difference in splenomegaly was observed between DEC-treated villagers and their untreated counterparts. Significant differences were reported in the rate of detectable microfilariae of Wuchereria bancroft!, but not of malaria, between the 2 groups. The number of DEC administrations and the period of time smce the first treatment played a significant role immunologicallv. Sienificant differences were observed in immunoalobulin (Ia) M and IaG levels and in the extent of splenom~galy between DEC-treated and untreated areas. Fi1aria.linfection associatedwith malaria resulted in higher spleen rates and size. W. bancrofti is a major contributor to splenomegaly in the Ok Tedi region, and sulenomenalv associatedwith bancroftian lilariasis can be reduced or controlled by low, well-spaced dosesbf DEC.” . Introduction
Malaria is considered to be the principle cause of illhealth in the Ok Tedi region of Western province, Papua New Guinea, and is assumed to be responsible for high rates of splenomegaly and hepatomegaly (TAUKURO& NURSE, 1979a, 1979b). The hiah rate of filariasis (34%) due to ‘Wuche&ia bancrofti reported by CATTANIkt al: f 1983) for the Star Mountains (immediate Ok Tedi area) was sunnorted bv the 13% incidence of microtilaraemia detected in daytime blood smearsfrom villagers around Atemkit. 1000 m above sea level. 5 vears earlier (TAUKURO et’al., 1980). The high rate of “daytime microfilaraemia (11.3%) observed amongst local employeesof Ok Tedi- Mining Limited during routine passive casedetection for malaria in 1982, a time of intense local recruitment from all parts of the Ok Tedi region, were consistent with the above reports (SCHUURKAMP et aZ., 1987a). A review in 1986 of the Wopkaimin population, the major linguistic group within the immediate Ok Tedi area, showed major declines in hepatomegaly, splenomegaly, enlarged lymph nodes, and malaria amongst others since 1982 (LOURIE, 1987). Overall, 16% had some degree of liver enlargement (LOURIE, 1987) compared to 77% during the 1982-1983baseline (CATTANI et al., 1983), and the prevalence of enlarged livers was reduced from 33% to 3%. This corresponded with a reduction in the prevalence of enlarged spleens in children under 10 years of age from the baseline level of 72.8% to 28.5% in 1986. Larger spleens were less frequently seen (16% of the whole sample had spleensof Hackett’s grade III or larger on follow-up). In general, the splenomegaly rate was reduced from 76.1% to 39.7% in 4 years. The reduction in averageenlarged spleen (AES) size (2.32 to 1.22) was highly significant. Rates of splenomegaly in adults varied with altitude: 80-90% for those living in the 610-765 m range above sea level and 68% at 1400 m (LOURIE, 1987). The findings of the Ok Tedi Health and Nutrition Project (LOURIE, 1987) were consistent with a reduced malarial load in the population due to malaria control activities implemented by Ok Tedi Mining Limited (SCHUURKAMP et al., 1987a, 198713). Filariasis is also highly endemic amongst the Ningerum alone the southern frinee of the Ok Tedi area. In 1978 a 47% rate of microfilariemia was reported amongst the north Ningerum in the 400-600 m range above sea level, and 28% in the foothills below (TAUKUROet al., 1980). Addressfor correspondence: Dr Gerrit Schuurkamp,Medical Department,Ok Tedi Mining Limited, P.O. Box 1, Tabubil, WesternProvince,PapuaNew Guinea.
It has been suggestedthat a substantial proportion of the acute febrile episodes reported by aid post orderlies in the areais due to filariasis. Inguinal lymphadenopathy was widespread throughout the population, presumably associatedwith leg sepsis,but in somecasesit was almost certainly a consequence of tilariasis. Despite the high rates of lilariasis in the region, the clinical manifestation of chronic illness (elephantiasis) was rare compared to that in non-Ningerum speaking villages along the Fly river south of Kiunga (TAUKURO& NURSE,1979b). TAUKURO et al. (1980) noted a ‘puzzling’ higher spleen rate (51%) in the Atemkit area of the Star Mountains, Papua New Guinea, amongst 104 villagers 10 years of age and older, despite a low rate of malaria parasitaemia (13%). Children under 10 years of age, on the other hand, demonstrated a higher malaria parasite rate (56%) and a somewhat lower spleen rate (44%). A decadelater the situation was unchanned at Atemkit in the over 10 years age group, with a spleen rate of 93% (39/42), a persistent low erade AES size of 2.1. and a 12% malaria parasite rate” (SCHUURKAMPet al.,’ 1990). Microtilariae (mf) were detected in 29% of these individuals, with the highest mean microfilaraemia recorded for the area, 138mf/20 ul. During the 1988 malariaifilariometric surveys of the Ok Tedi coveragearea (3000 km2) identical low malaria parasite rates (14%) were found’ both in populations treated with diethvlcarbamazine IDEC) and in untreated populations, but ihe spleen rates were dissimilar (47% and 76% respectively) (SCHUURKAMP et aE., 1990). The ‘puzzling’ high spleen rate associated with low malaria parasitaemia in older individuals was observed as recently as 1990 in 27 Kawentinkin villagers not receiving DEC at Atemkit. These villagers demonstrated rates similar to those reported in 1978 for the same general area: 56% splenomegaly, 15%malaria and 82% microfilaraemic, compared to rates of 47% (35/75) splenomegaly, 7% (5/75) malaria and 19% (14/75) microfilaria in villagers in the samecommunitv treated with DEC annuallv since 1988. Hepatomegaly is strongly associated with splenomegaly in the Star Mountains of Western province, unlike the Middle Flv region directlv to the south (TAUKURO et al., 19gO; ~CATTANI et al., 1983).\ The microfilaricidal action of DEC depends upon the proper function of the humoral and cellular immune mechanism of the host. Most of the mf in the blood are destroyed by the reticuloendothelial cells of the liver (WHO, 1984). Information is lacking concerning the association of immunological changes and splenomegaly in humans with
532 filariasis. Splenic hyperplasia and antigen-reactive spleen cells have been reported in jirds sometime after infection with Diataelonema viteae (ABRAHAMet al.. 1986). Snlenic suppre&ion of microfilaraemia has been demonstrated in almost every primate species infected with Loa, Brugia and Mansonella, and most reports deal with mf sequestering or being filtered from the blood bv the soleen, causiig gross morphological changesor abnormal&es of the spleen (ORIHEL& EBERHARD,1985). Three postulates were proposed in 1988 for investigation for the Ok Tedi area: (i) that splenomegalyin the Ok Tedi area, where chronic tilariasis is known to exist, is not due to malaria alone; (ii) that splenomegaly would most probably persist or be enhanced by filarial infection; and (iii) that DEC might be effective in the control of splenomegaly. Materials and Methods Field procedures
Treatment with diethylcarbamazine citrate (DEC), in 50 mg tablet form, commenced in June 1986. A dose of 6 mg per kg body weight was given as a single dose at semi-annual intervals during the initial 2-year phase 1 introductory programme involving 5 villages (group 1) (SCHUURKAMP et al., 1990). The successful phase 1 programme was expanded into an annual single-doseadministration of DEC over a larger area comprising an additional 7 villages (group 2>. Drugging-commenced at 20:O0. after villagers had eaten sufficient to tolerate drug. ingestion and as&re maximum efficiency of the drug on active circulating parasites. Individuals under 15 kg body weight, pregnant femalesand the ill were excluded. The occasional side-effects often associated with DEC and the release of foreign protein into the blood from dead mf were subdued by administering an antihistamine with DEC treatment during the first 2 drug cycles. Injectable cortisone and oxygen were available in case of hypersensitivity or anaphylactic shock. Villagers were monitored for 24-48 h after treatment. Grotto 3 consisted of other inhabitants (immigrants or tempoiary visitors) of the 12 survey villages, who had received at least one DEC treatment since 1986. Filariolmalariometric
Antigen and antibody were allowed to react for 6 min and the amount of light scatteredwas measuredand compared to a standard calibration curve constructed weekly, using Behring standard sera. Internal (serum) controls were included with each run. and a standard Pamta New Guinea serum pool of known Ig concentration was included in selectedruns. Test samples were run in batches of 32; 200 1 were reauired for each test. When the initial results ! ell outside the range of the calibration curve, appropriate dilution was carried out by the instrument. All results, expressed in mg/dl, were converted to loglo values before statistical analysis, since Ig values approximate to a log normal distribution. Statistical analysis
All information from field and laboratory surveys was entered into a computer database(Borland-Ansa’s Paradox@, version 3.5) and retrieved information assessed statistically with the aid of Statistical Analysis Systems@ software version 5.18 (SAS Institute Inc.) on a Data General network MV@ computer. Fisher’s exact test and x2 were used to test differences in proportions and determine significance levels. x2, degreesof freedom (df) and probability (P) values are reported for each observation. Assessment of serological data was based on log data evaluations by analysis of variance (ANOVA) -using Tukey’s studentized range (HSD) test for the 4 variables IgA, IgM, IgG and spleen enlargement. Results Malaria and filariasis compared with splenomegaly before and after treatment
Table 1 summarizes observations in the 12 villages involved in the DEC treatment programme. A significant improvement was seen after treatment in villagers with and without splenomegaly when assessed for the presence of detectable microfilaraemia (x*=42.192 for 1 df; P
