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Changes in the peripheral blood eosinophil count in falciparum malaria
Acta Tropica, 48(1991)243-245 Elsevier
243
ACTROP 00116
Short Communication
Changes in the peripheral blood eosinophil count in falciparum malaria T i m o t h y M . E . D a v i s 1'2, M a y H o 1, W i c h a i S u p a n a r a n o n d 1, S o r n c h a i L o o a r e e s u w a n 1, S a s i t h o n P u k r i t t a y a k a m e e 1 and N i c h o l a s J. White 1'2 1Bangkok Hospital for Tropical Diseases, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand, and 2Tropical Medicine Unit, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, U.K. (Received 7 March 1990; accepted 10 May 1990) Key words: Eosinophils; Malaria; Plasmodiumfaleiparum; Eosinopenia; Eosinophilia
Unlike other parasitic infections, acute malaria does not provoke a prompt eosinophilia. However, there is some evidence that sequential changes in eosinophil count result from Plasmodiumfaleiparum infection (Lowe, 1944; Reiley and Barrett, 1971; Abdalla, 1988). To characterise the extent, timing and features associated with such changes, we studied 21 slide-positive Thai adults (12 males, 9 females; mean age 21 years) who had at least four differential white cell counts over a period of more than 28 days from admission. Thirteen patients were assessed as severe, with peripheral parasitaemia > 250 000 asexual forms/121 and/or renal, neurological or hepatic complications (WHO, 1986); eight were uncomplicated. No patient was atopic or had a recent history of allergy. All responded to quinine or mefloquine treatment and all were afebrile and aparasitaemic at discharge. No recrudescences, drug sensitivity reactions or bacterial infections were detected during follow-up. Absolute eosinophil counts were calculated from the total leucocyte count (using a Neubauer chamber) and percentage differential (from examination of Wright-stained blood films). A single count was obtained from each of 35 randomly-selected healthy adult Thais who were slide-negative for malaria and from the same rural areas as the patients. Statistical analysis was by nonparametric tests and data are medians and (95% confidence intervals) (Siegel and Castellan, 1988). No eosinophils were seen on microscopic examination of admission blood films from 9 of 21 patients. Admission counts (54/121 [0-81]) were all lower than those of controls (255/t21 [147-416]; Wilcoxon, p < 0.0001) but were similar to values at discharge (91/121 [9-172]; Friedman )~2 test, p > 0.60) a median of 5 days [4-8] later (see Correspondence address; Dr T. Davis, Bangkok Hospital for Tropical Diseases, Faculty of Tropical Medicine, 420/6 Rajvithi Rd, Bangkok 10400, Thailand. 0001-706X/91/$03.50 © 1991 Elsevier Science Publishers B.V. (Biomedical Division)
244 Ecoinophll count (/:~L) 1600 1400 1200 1000 8O0
6O0 400 20O
01'
~ Admission
t Discharge
i Convalescence
[ Controls
Fig. 1. Serial eosinophil counts in 21 patients with falciparum malaria followed for at least four weeks, and in 35 healthy controls. Data are medians and 95% confidence intervals (c.i.). The values at the time
of discharge are a median (95% c.i.) of 5 days (4-8) after admission; convalescentvalues are the maximum counts achieved during follow-upof a median of 35 days (29-37) post-admission.
Fig. 1). The eosinophil count rose during convalescence in all patients. The maximum counts (913/~1 [651-1395]), a median of 35 days [29-37] post-admission, were greater than those on admission and discharge (Friedma~ X2 test, (p < 0.025; see Fig. 1) and of the controls ( p < 0.0001). There was no significant difference between the admission eosinophil counts of the patients with severe (39/p.1 [0-82]) and uncomplicated (71/~1 [0-324]) infections (Wilcoxon, p = 0.19). The severe cases had a similar median rise in count from admission to peak (913/ktl [222-1460]) to that of the uncomplicated group (948/p.1 [276-3990]; p > 0.50) and there was no correlation between the rise and admission haematocrit, parasitaemia, or serum bilirubin or creatinine ( - 0 . 2 9 < rs<0.13, n = 2 1 , p>0.2). Our results demonstrate that a biphasic change in the peripheral blood eosinophil count results from P.falciparum infection in man. Acute disease is associated with an eosinopaenia which lasts beyond clearance of fever and parasitaemia. A posttreatment rise in eosinophil count, sometimes to very high levels, occurs late in convalescence. This pattern appears unrelated to severity of infection, may reflect aspects of the pathophysiology of falciparum malaria, and raises practical management issues. Eosinopaenia, which has been found in African children with acute malaria using similar haematological methods (Abdalla, 1988), suggests suppressed eosinophil production or release from the marrow, or enhanced peripheral removal. Since histological studies have shown increased bone marrow precursors in both complicated and uncomplicated malaria (Srichaikul et al., 1967), eosinophil maturation is probably abnormal, analogous to malaria-related dyserythropoiesis. The eosinopaenia of acute inflammation is associated with eosinophil migration to sites involved (Bass, 1977) but there is little evidence of tissue accumulation in falciparum malaria. Eosinophilia after treatment for malaria has been reported previously where there was no appropriate reference range (Lowe, 1944; Reiley and Barrett, 1971). Nevertheless, our results confirm that eosinophilia is common in convalescence, typically reaching a peak more than a month after hospital discharge. This time lag suggests that antimalarial drug sensitivity is not implicated. Since counts consistently exceeded
245 those of controls, intestinal parasites are also an unlikely cause. Several cytokines stimulate eosinophil proliferation and function, and changes in their circulating concentrations could modulate eosinophil levels. Alterations in interleukin 2 production in malaria parallel the changes in eosinophil count in our patients and are also independent of disease severity (Ho et al., 1988). Eosinophil secretory products inhibit multiplication of P. falciparurn in vitro suggesting that eosinophilia contributes to malarial immunity (Waters et al., 1987). Studies of eosinophil activation and secretion in vivo in relation to their numbers in the circulation would be of value in determining the importance of the eosinophil in this regard. One third of Thai patients with falciparum malaria will develop P. vivax infection 15-65 days after quinine treatment (Looareesuwan et al., 1987). The role of the eosinophil in preventing both activation of vivax malaria and late recrudescence of falciparum malaria (neither of which was found in any of our patients during follow-up) also warrants further study. These data suggest that acute malaria depresses the peripheral blood eosinophil count even in mild infections. This might mask co-incident conditions normally associated with eosinophilia. A raised post-treatment count is likely to be due to malaria per se. Antimalarial drug sensitivity is a rare cause but other evidence of allergy would be expected. Helminthic infection may be present, but, when the patient is asymptomatic and from an area endemic for intestinal parasites, further investigation and treatment could be delayed until at least 6 weeks after admission.
Acknowledgements We thank the Directors and staff of Pra Pokklao Hospital, Chantaburi, Thailand and Paholpolpayuhasena Hospital, Kanchanaburi, Thailand, Dr. Kyle Webster, A F R I M S , Bangkok, and Professors Danai Bunnag and Tranakchit Harinasuta for co-operation and support. The study is part of the Wellcome-Mahidol UniversityOxford Tropical Medicine Research Programme funded by the Wellcome Trust of Great Britain. M.H. is a Clinical Investigator of the Alberta Heritage Foundation for Medical Research, Canada.
References Abdalla, S. (1988) Peripheral blood and bone marrow leucocytes in Gambian children with malaria: Numerical changes and evaluation of phagocytosis. Ann. Trop. Paed. 8, 250-258. Bass, D.A. (1977) Reproduction of the eosinopaenia of acute infection by passive transfer of a material obtained from inflammatory exudate. Infect. Immun. 15, 410-416. Ho, M., Webster, H.K., Green, B., Looareesuwan, S., Kongcharoen, S. and White, N.J. (1988) Defective production of and response to IL-2 in acute falciparum malaria. J. Immunol. 141, 2755-2759. Looareesuwan, S., White, N.J., Chittamas, S., Bunnag, D. and Harinasuta, T. (1987) High rate of Plasmodium vivax relapse following treatment of falciparum malaria in Thailand. Lancet ii, 1052-1055. Lowe, T.E. (1944) Eosinophilia in tropical disease. Med. J. Aust. 1,453-462. Reiley, C.G. and Barrett, O. (1971) Leucocyte response in acute malaria. Am. J. Med. Sci. 262, 153-159. Siegel, S. and Castellan, N.J. (1988) Nonparametric Statistics for the Behavioural Sciences. McGraw-Hill, New York, NY.
243
ACTROP 00116
Short Communication
Changes in the peripheral blood eosinophil count in falciparum malaria T i m o t h y M . E . D a v i s 1'2, M a y H o 1, W i c h a i S u p a n a r a n o n d 1, S o r n c h a i L o o a r e e s u w a n 1, S a s i t h o n P u k r i t t a y a k a m e e 1 and N i c h o l a s J. White 1'2 1Bangkok Hospital for Tropical Diseases, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand, and 2Tropical Medicine Unit, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, U.K. (Received 7 March 1990; accepted 10 May 1990) Key words: Eosinophils; Malaria; Plasmodiumfaleiparum; Eosinopenia; Eosinophilia
Unlike other parasitic infections, acute malaria does not provoke a prompt eosinophilia. However, there is some evidence that sequential changes in eosinophil count result from Plasmodiumfaleiparum infection (Lowe, 1944; Reiley and Barrett, 1971; Abdalla, 1988). To characterise the extent, timing and features associated with such changes, we studied 21 slide-positive Thai adults (12 males, 9 females; mean age 21 years) who had at least four differential white cell counts over a period of more than 28 days from admission. Thirteen patients were assessed as severe, with peripheral parasitaemia > 250 000 asexual forms/121 and/or renal, neurological or hepatic complications (WHO, 1986); eight were uncomplicated. No patient was atopic or had a recent history of allergy. All responded to quinine or mefloquine treatment and all were afebrile and aparasitaemic at discharge. No recrudescences, drug sensitivity reactions or bacterial infections were detected during follow-up. Absolute eosinophil counts were calculated from the total leucocyte count (using a Neubauer chamber) and percentage differential (from examination of Wright-stained blood films). A single count was obtained from each of 35 randomly-selected healthy adult Thais who were slide-negative for malaria and from the same rural areas as the patients. Statistical analysis was by nonparametric tests and data are medians and (95% confidence intervals) (Siegel and Castellan, 1988). No eosinophils were seen on microscopic examination of admission blood films from 9 of 21 patients. Admission counts (54/121 [0-81]) were all lower than those of controls (255/t21 [147-416]; Wilcoxon, p < 0.0001) but were similar to values at discharge (91/121 [9-172]; Friedman )~2 test, p > 0.60) a median of 5 days [4-8] later (see Correspondence address; Dr T. Davis, Bangkok Hospital for Tropical Diseases, Faculty of Tropical Medicine, 420/6 Rajvithi Rd, Bangkok 10400, Thailand. 0001-706X/91/$03.50 © 1991 Elsevier Science Publishers B.V. (Biomedical Division)
244 Ecoinophll count (/:~L) 1600 1400 1200 1000 8O0
6O0 400 20O
01'
~ Admission
t Discharge
i Convalescence
[ Controls
Fig. 1. Serial eosinophil counts in 21 patients with falciparum malaria followed for at least four weeks, and in 35 healthy controls. Data are medians and 95% confidence intervals (c.i.). The values at the time
of discharge are a median (95% c.i.) of 5 days (4-8) after admission; convalescentvalues are the maximum counts achieved during follow-upof a median of 35 days (29-37) post-admission.
Fig. 1). The eosinophil count rose during convalescence in all patients. The maximum counts (913/~1 [651-1395]), a median of 35 days [29-37] post-admission, were greater than those on admission and discharge (Friedma~ X2 test, (p < 0.025; see Fig. 1) and of the controls ( p < 0.0001). There was no significant difference between the admission eosinophil counts of the patients with severe (39/p.1 [0-82]) and uncomplicated (71/~1 [0-324]) infections (Wilcoxon, p = 0.19). The severe cases had a similar median rise in count from admission to peak (913/ktl [222-1460]) to that of the uncomplicated group (948/p.1 [276-3990]; p > 0.50) and there was no correlation between the rise and admission haematocrit, parasitaemia, or serum bilirubin or creatinine ( - 0 . 2 9 < rs<0.13, n = 2 1 , p>0.2). Our results demonstrate that a biphasic change in the peripheral blood eosinophil count results from P.falciparum infection in man. Acute disease is associated with an eosinopaenia which lasts beyond clearance of fever and parasitaemia. A posttreatment rise in eosinophil count, sometimes to very high levels, occurs late in convalescence. This pattern appears unrelated to severity of infection, may reflect aspects of the pathophysiology of falciparum malaria, and raises practical management issues. Eosinopaenia, which has been found in African children with acute malaria using similar haematological methods (Abdalla, 1988), suggests suppressed eosinophil production or release from the marrow, or enhanced peripheral removal. Since histological studies have shown increased bone marrow precursors in both complicated and uncomplicated malaria (Srichaikul et al., 1967), eosinophil maturation is probably abnormal, analogous to malaria-related dyserythropoiesis. The eosinopaenia of acute inflammation is associated with eosinophil migration to sites involved (Bass, 1977) but there is little evidence of tissue accumulation in falciparum malaria. Eosinophilia after treatment for malaria has been reported previously where there was no appropriate reference range (Lowe, 1944; Reiley and Barrett, 1971). Nevertheless, our results confirm that eosinophilia is common in convalescence, typically reaching a peak more than a month after hospital discharge. This time lag suggests that antimalarial drug sensitivity is not implicated. Since counts consistently exceeded
245 those of controls, intestinal parasites are also an unlikely cause. Several cytokines stimulate eosinophil proliferation and function, and changes in their circulating concentrations could modulate eosinophil levels. Alterations in interleukin 2 production in malaria parallel the changes in eosinophil count in our patients and are also independent of disease severity (Ho et al., 1988). Eosinophil secretory products inhibit multiplication of P. falciparurn in vitro suggesting that eosinophilia contributes to malarial immunity (Waters et al., 1987). Studies of eosinophil activation and secretion in vivo in relation to their numbers in the circulation would be of value in determining the importance of the eosinophil in this regard. One third of Thai patients with falciparum malaria will develop P. vivax infection 15-65 days after quinine treatment (Looareesuwan et al., 1987). The role of the eosinophil in preventing both activation of vivax malaria and late recrudescence of falciparum malaria (neither of which was found in any of our patients during follow-up) also warrants further study. These data suggest that acute malaria depresses the peripheral blood eosinophil count even in mild infections. This might mask co-incident conditions normally associated with eosinophilia. A raised post-treatment count is likely to be due to malaria per se. Antimalarial drug sensitivity is a rare cause but other evidence of allergy would be expected. Helminthic infection may be present, but, when the patient is asymptomatic and from an area endemic for intestinal parasites, further investigation and treatment could be delayed until at least 6 weeks after admission.
Acknowledgements We thank the Directors and staff of Pra Pokklao Hospital, Chantaburi, Thailand and Paholpolpayuhasena Hospital, Kanchanaburi, Thailand, Dr. Kyle Webster, A F R I M S , Bangkok, and Professors Danai Bunnag and Tranakchit Harinasuta for co-operation and support. The study is part of the Wellcome-Mahidol UniversityOxford Tropical Medicine Research Programme funded by the Wellcome Trust of Great Britain. M.H. is a Clinical Investigator of the Alberta Heritage Foundation for Medical Research, Canada.
References Abdalla, S. (1988) Peripheral blood and bone marrow leucocytes in Gambian children with malaria: Numerical changes and evaluation of phagocytosis. Ann. Trop. Paed. 8, 250-258. Bass, D.A. (1977) Reproduction of the eosinopaenia of acute infection by passive transfer of a material obtained from inflammatory exudate. Infect. Immun. 15, 410-416. Ho, M., Webster, H.K., Green, B., Looareesuwan, S., Kongcharoen, S. and White, N.J. (1988) Defective production of and response to IL-2 in acute falciparum malaria. J. Immunol. 141, 2755-2759. Looareesuwan, S., White, N.J., Chittamas, S., Bunnag, D. and Harinasuta, T. (1987) High rate of Plasmodium vivax relapse following treatment of falciparum malaria in Thailand. Lancet ii, 1052-1055. Lowe, T.E. (1944) Eosinophilia in tropical disease. Med. J. Aust. 1,453-462. Reiley, C.G. and Barrett, O. (1971) Leucocyte response in acute malaria. Am. J. Med. Sci. 262, 153-159. Siegel, S. and Castellan, N.J. (1988) Nonparametric Statistics for the Behavioural Sciences. McGraw-Hill, New York, NY.