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ABO blood groups and malaria related clinical outcome.

INTRODUCTION

The association of genetic markers with malaria has been the subject of numerous investigations, since the protection afforded by sickle-cell hemoglobin against infection by falciparum malaria parasite. A broad range of available evidence suggests that the origin, distribution and relative proportion of ABO blood groups in humans may have been directly influenced by selective genetic pressure from Plasmodium falciparum infection (1). Clinical reports of ABO blood groups and P. falciparum infection, reveals a correlation between disease severity and ABO groups. However, several studies undertaken have been unable to link ABO blood groups to the incidence of malaria or to the repeat attacks of malaria (2,3).

Recent studies of the pathogenesis of malaria have shown that parasite triggered red blood cell rosette formation is associated with the severity of clinical disease and malaria (4,5). Rosetting was established as a P. falciparum virulence factor, the expression of which is modified by a variety of host factors. Anti-rosetting activity, presumably mediated by antibodies, was found in sera from patients in malaria endemic areas, and it was demonstrated that such activity was more abundant in individuals with uncomplicated malaria than in those with cerebral disease, suggesting that humoral immunity protects against rosette formation in vivo. Erythrocytes from individuals with sickle-cell trait, [alpha]- and [beta]-thalassemia trait or with HbE formed smaller and weaker rosettes than did normal HbAA red blood cells. Recently, even P. vivax infection has been reported with clinical severity. There is a paucity of hospital-based, comparative studies to investigate the relationship between blood group types and severity of malarial infections. This study was undertaken to fill up the lacunae in understanding the relationship between blood group phenotypes and malaria in a hospital environment. The objectives of the present study were: (i) to screen and estimate the incidence of malaria in a hospital environment; and (ii) to correlate the blood groups and the clinical presentations including outcome in malaria patients.

MATERIAL & METHODS

This study was conducted during period from October 2007 to September 2008 on blood samples from patients presented with malaria and confirmed as positive in St. John's Medical College Hospital. The diagnosis was based on peripheral smear and quantitative buffy coat method (QBC). Blood group was determined by forward and reverse method. Hematological parameters which included hemoglobin, total leukocyte count and platelet count of each patient were done on automated cell counter. The demographic details of the patients and clinical details were obtained from case records of the patients. Malarial species and the severity of clinical course were correlated with blood groups.

The clinical course between the different groups was compared using the following parameters for severe infection:

* a parasitic load of >10/1000 RBCs

* severe anemia with hemoglobin <6 g% * platelet count of <10,000/[mm.sup.3]

* hepato or splenomegaly or

* clinical signs of severe malaria such as fever >101[degrees]F and

* other organ involvement

RESULTS

Among 11,552 smears screened during this period, 100 patients turned out to be positive and all the 100 samples were evaluated by both QBC method and thick and thin Leishman stained smears. The species of malarial parasites were P. falciparum (Pf) (63%); P. vivax (Pv) (37%) and 11 patients had mixed infection of both Pv and Pf.

Among 100 patients, 22 were 'A' positive, 42 'B' positive, 35 'O' positive and 1 'AB' positive. Irrespective of the blood group, the number of patients affected by P. falciparum was more than P. vivax. The only patient who had AB positive group had P. falciparum and was hospitalized as Intensive Care Unit patient. Among the patients who had mixed infection, 6 had 'A' group, 3 'B' group and 2 'O' group.

Malaria affected all age groups and the age ranged from 1 to 71 yr old (M : F 8 : 2). The number of adults affected was more (n = 82) than the children (n = 18). Among the adults, the prevalence was more in the younger age group. Among 18 in the pediatric age group, 6 were treated in ICU, while the rest were treated as inpatients. One year old child, though affected by Pv, was in ICU as the hemoglobin was low (4.9 g%).

Although the majority of them were inpatients (98%) and only 2 were managed as outpatients, both of them were affected by P. falciparum. Among 98% hospitalized patients, 37% were affected by P. vivax and 61% by P. falciparum. When the clinical severity was compared with blood groups, it was observed that 'O' group had an advantage (Fig. 1). The laboratory investigations are summarized in Table 1.

DISCUSSION

Malaria has been known since antiquity. Much new information has emerged since a relationship between ABO and malaria was first suggested >40 years ago (6). However, the correlation of severity of malarial infection to the patient's blood group has been of recent interest in the quest for the answers to the factors influencing clinical course of the disease. The observation by Miller et al (7) that human erythrocytes lacking the Duffy blood group antigens are refractory to invasion by P. vivax parasites indicate the usefulness of studying the association of blood group with malaria. In the Indian scenario, the literature relating to malaria and the blood groups are sparse and have mixed results. Thakur and Verma (8) in their study, concluded that ABO blood groups do not show differential susceptibility to malaria. Joshi et al (9) reported no correlation between ABO blood groups and malaria in Delhi. Other studies indicated a possible relationship (10). The present study was attempted to correlate the blood groups and the clinical presentations in malaria patients.

Among the adults, this study showed different age groups had no significant correlation with incidence of malaria. All age groups and both genders were affected. However, the course of the disease in children was severe than that among adults. In a cross-sectional study by Eli et al (11), influence of age and other factors that affect clinical outcome of P. falciparum malaria in non-immune patients was evaluated. In their study of 135 patients with P. falciparum malaria, 84 (62%) were <40 yr old, and only 5% developed severe malaria, compared with 18% who were [greater than or equal to] 40 yr old (odds ratio, 4.29); moreover, all deaths occurred in the latter group. Male subjects did not differ from female subjects with regard to severity of disease. Similarly, in this study, the severity did not differ between males and females. Red blood cells of children with severe malaria-associated anemia (SMA) have acquired deficiencies in the complement regulatory proteins complement receptor 1 (CR1, CD35) and decay accelerating factor (DAF, CD55). Deficiencies in red blood cell CR1 and CD55 in children with SMA were accompanied by a marked decline in immune complex binding capacity and increased C3b deposition in vivo and ex vivo. Importantly, these changes were specific because they were not seen in red blood cells of children with cerebral malaria or their controls. These data suggest that the decline in red blood cell CR1 and CD55 seen in children with SMA were of physiologic significance and may predispose erythrocytes to complement-mediated damage and phagocytosis in vivo.

All patients presented with fever and chills. The initial presentation of fever and chills was present irrespective of the blood groups. However, the number of ICU admissions was more in 'B' group than other groups, and also associated with P. falciparum infection. Among the hospitalized adult patients, 4% had hemoglobin below 6 g/dl including both P. falciparum and P. vivax infections. Though the predominant population was adults, in the children who were affected, hemoglobin ranged from 4.9 to 13.8 g%. The reason for the anemia was because macrophages not only clear infected erythrocytes but also phagocytes destroyed uninfected red blood cells during malaria infections. It has been observed in a prospective study conducted in Orissa that the clinical features in Indian children differed from those reported in most studies that involved an African population. Multiple organ dysfunctions emerged as an important presenting feature and a new predictor of death in childhood malaria though anemia causes morbidity (12) with malaria. Anemia was also seen with P. vivax infection. A one year old baby with P. vivax had a hemoglobin value of 4.9 g% was treated in ICU indicating other factors also played a role.

Leucocytosis was observed only in 5% of the patients, though malaria is considered to be an infection. Areas that cannot afford even simple laboratory diagnostic tests often use only a history of fever which is subjective as the indication for malaria. Using Giemsa stained blood smears from children in Malawi, one study showed that unnecessary treatment for malaria was significantly decreased when clinical predictors including temperature, pallor and splenomegaly were used as treatment indicators (13) (sensitivity increased from 21 to 41%).

Platelet count was decreased in 80% of patients. In P. falciparum infection platelet count dropped to <20,000/ [mm.sup.3] irrespective of the blood group. When correlated with parasitic load, it did not show any correlation. It has been noted that the presence of thrombocytopenia in an endemic area should alert malaria infection. Both non-immunological destruction and immune mechanisms are implicated in the pathogenesis of thrombocytopenia.

* Specific platelet-associated IgG antibodies that bind directly to the malarial antigen in the platelets play a role in the lysis of platelets.

* Elevated M-CSF levels in malaria, by increasing macrophage activity may mediate platelet destruction.

* Oxidative stress damage-decreased platelet superoxide-dismutase and glutathione peroxidase activity and high platelet lipid peroxidation.

Clinical severity, rather than incidence or prevalence of detectable parasitemia, is a more relevant outcome to assess ABO group and survival. Studies reporting clinical features such as cerebral malaria carry more weight than those reporting only laboratory markers such as percent parasitemia, because the latter does not always predict survival. Among those with a well-developed humoral immunity, there is little correlation between high circulating parasitemia and severity of illness. Plasmodium falciparum infection increases the serum levels of IgM and IgG antibodies, and also IgE in individuals living in endemic areas. The association of high anti PF IgE levels with a reduced risk of developing clinical malaria suggests the involvement of IgE in protection (14).

In 1998, Fischer and Boone (15) reported favourable outcomes for group 'O' individuals compared with group 'A' among 489 patients in Zimbabwe with P. falciparum malaria. They studied 209 outpatients and 280 severely ill inpatients. Coma was 3-times more common among group 'A' individuals compared with non-A persons (9 of 104 group 'A' vs 11 of 385 with non-A blood, p = 0.008; odds ratio, 3.6). Because patients with coma are at a higher risk for death, this study supports the hypothesis that group 'O' individuals may have a survival advantage in severe malaria. However, the sample size was insufficient to observe an effect of 'ABO' group on survival (15).

Lell et al (16) compared 100 cases of severe P. falciparum malaria with 100 cases of mild malaria in Gabon. Severe malaria was defined as either hyperparasitemia with >0.25 x [10.sup.12] infected red blood cells (RBCs) per L or >10% parasitemia; or severe anemia with Hb <5 g/L; or clinical signs of severe malaria. Mild malaria cases had minimal laboratory abnormalities and were treated as outpatients. The ratio of group 'A' to group 'O' in patients with severe malaria was 0.50, but was only 0.17 among those with mild malaria (3-fold relative risk). Among all group 'A' individuals, 71% had severe malaria and only 29% mild malaria (p<0.01). In contrast, among all group 'O' cases, 46% had severe malaria and 54% mild malaria (p<0.21). In Sri Lanka, Pathirana et al (5) assessed 243 adult cases (mean age, 29.8 yr) of P. falciparum malaria (163 mild, 80 severe) compared with 65 control patients with other infections (5). The proportion of group 'O' in mild malaria cases was 48%, but only 24% in severe malaria cases. The distribution of ABO groups was significantly different in severe malaria syndromes compared with uncomplicated malaria or the control population (p<0.001). Once again, a case of severe malaria was nearly 3-times as likely to be in group 'A' as O (p =0.005). This study provided the strongest statistical evidence of an association between ABO and disease severity in P. falciparum infection.

Udomsangpetch et al (17) showed a strong association between rosette formation and ABO blood group, with group 'A' and group 'B' RBCs (A > B) forming rosettes more than group 'O' cells in each of 8 tested strains (p < 0.001). Rowe et al (18) confirmed that among 154 isolates, RBCs from group 'O' patients rosetted less (median rosette frequency, 2%; range, 0-45%) than those from group 'A' (median, 7%; range, 0-82%; p <0.01) or group 'AB' (median, 11%; range, 0-94%; p<0.03). Chotivanich et al (19) found the highest relative rosette ratios in vitro among RBCs from healthy donors who were group 'A' (2.7 [+ or -] 1.4) and 'B' (2.4 [+ or -] 1.1) compared with group 'O' (1.6 [+ or -] 0.7; p = 0.05). Most recently, Barragan et al (20) confirmed that group 'A' targets formed the strongest rosettes. In addition, they reported that RBCs of group 'A' enzymatically converted to RBCs, of group 'O' and Bombay RBCs rosetted minimally and to the same degree. Thus, potentiation of rosetting appears specific (but not exclusive) to A and B antigens.

The adherence of parasitized RBCs to other cells is central to the pathophysiology of severe malaria syndromes including cerebral malaria, respiratory failure, multiorgan failure, and death. Parasitized RBCs adhere to the vasculature through a process termed "sequestration," closely mimicking inflammatory leukocyte attachment. Furthermore, half of infected RBC isolates form occlusive intravascular aggregates, which consist not only of infected RBCs bound to each other "autoagglutinates" but also infected RBCs bound to uninfected RBCs "homotypic RBC rosettes" and/or to platelets "heterotypic RBC rosettes". Sequestration and rosette formation impair blood flow, causing tissue ischemia and cell death. Not surprisingly, in vitro rosetting is more pronounced in parasite strains derived from patients with severe disease, particularly in cases of cerebral malaria. In addition, host ABO group may affect other aspects of malaria pathogenesis.

Malaria is known to have affected many erythrocyte genes, including those concerned with globin synthesis, membrane proteins, and RBC enzymes. Given the importance of RBCs in malaria, an influence on genes encoding the most abundant antigens on the RBC membrane such as blood groups is expected. It is also difficult to dissociate the role played by ABO sugars from the contribution of other glycosylated adhesion molecules. The present study including both P. falciparum and P. vivax infections provides supporting evidence in favour of an effect of ABO group on disease severity as 'O' group provides advantage over non 'O' groups.

REFERENCES

(1.) Christine M Cserti, Walter H Dzik. The ABO blood group system and Plasmodium falciparum malaria. Blood 2007; 110(7): 2250-8.

(2.) Facer CA, Brown J. ABO blood groups and falciparum malaria. Trans R Soc Trop Med Hyg 1979; 73: 599-600.

(3.) Singh N, Shukla MM, Uniyal VP, Sharma VP. ABO blood groups among malaria cases from District Mandla, Madhya Pradesh. Indian J Malariol 1995; 32: 59-63.

(4.) Treutiger CJ, Hedlund I, Helmby H, Carlson J, Jepson A, Twamasi P, Kwiatkowski D, Greenwood BM, Wahlgren M. Rosette formation in Plasmodium falciparum isolates and antirosette activity of sera from Gambian with cerebral or uncomplicated malaria. Am J Trop Med Hyg 1992; 46: 503-10.

(5.) Pathirana SL, Alles HK, Bandara S, Phone-kyaw M, Perera MK, Wickremasinghe AR, Mendis KN, Handunnetti SM. ABO blood group types and protection against severe Plasmodium falci-parum malaria. Ann Trop Med Parasitolol 2005; 99: 119-26.

(6.) Allison AC. Protection afforded by sickle cell trait against subtertian malarial infection. Br Med J 1954; 1: 290-4.

(7.) Miller LH, Mason SJ, Dvorak JA, McGinniss MH, Rothman IK. Erythrocyte receptors for Plasmodium knowlesi malaria: duffy blood groups determinants. Science 1975; 189: 561-3.

(8.) Thakur A, Verma IC. Malaria and ABO blood groups. Indian J Malariol 1992; 29: 241-4.

(9.) Joshi H, Raghavendra K, Subbarao, Sarala K, Sharma VP. Genetic markers in malaria patients in Delhi. Indian J Malariol 1987; 24(1): 33-8.

(10.) Singh IP, Walter H, Bhasin MK, Bhardwaj V, Sudhakar K. Genetic markers and malaria observations in Gujarat, India. Human Heredity 1986; 36: 31-6.

(11.) Schwartz E, Sadetzki S, Murad H, Raveh D. Age as a risk factor for severe Plasmodium falciparum malaria in non-immune patients. Clin Infect Dis 2001; 33: 1774-7.

(12.) Tripathy R, Parida S, Das L, Mishra DP, Tripathy D, Dass MC, Chen H, Maguire JH, Panigrahi P. Clinical manifestations and predictors of severe malaria in Indian children. Pediatrics 2007; 120(3): 454-60.

(13.) Redd SC, Kazembe PN, Luby SP, Nwanyanwu O, Hightower AW, Ziba C, Wirima JJ, Chitsulo L, Franco C, Olivar M. Clinical algorithm for treatment of Plasmodium falciparum malaria in children. Lancet 1996; 347(8996): 223-7.

(14.) Duarte J, Deshpande P, Guiyedi V, Mecheri S, Fesel C, Cazenave PA, Mishra GC, Kombalia M, Pied S. Total and functional parasite specific IgE responses in Plasmodium falciparum-infected patients exhibiting different clinical status. Malar J 2007; 6: 2875-6.

(15.) Fischer PR, Boone P. Short report: severe malaria associated with blood group. Am J Trop Med Hyg 1998; 58(1): 122-3.

(16.) Lell B, May J, Schmidt-Ott RJ, Lehman LG, Luckner D, Greve B, Bienzle U, Kremsner PG. Plasmodium falciparum values with similar superscipt alphabets do not differ significantly rosetting is associated with malaria severity in Kenya. Infect Immun 1995; 63: 2323-6.

(17.) Udomsanpetch R, Thanikkul K, Pukrittayakamee S, White NJ. Rosette formation by Plasmodium vivax. Trans R Soc Trop Med Hyg 1995; 89(6): 635-7.

(18.) Rowe A, Obeiro J, Newbold CI, Marsh K. Plasmodium falciparum values rosetting is associated with malaria severity in Kenya. Infect Immun 1995; 63: 2323-6.

(19.) Chotivanich KT, Udomsangpetch R, Pipitaporn B, Angus B, Suputtamongkol Y, Pukrittayakamee S, White NJ. Rosetting characteristics of uninfected erythrocytes from healthy individuals and malaria patients. Ann Trop Med Parasitol 1998; 92(1): 45-56.

(20.) Barragan A, Kremsner PG,Wahlgren M. Blood group A antigen is a co receptor in Plasmodium falciparum rosetting. Infect Immun 2000; 68: 2971-5.

Deepa [1], Vanamala A. Alwar [1], Karuna Rameshkumar [1] & Cecil Ross [2]

[1] Department of Clinical Pathology; [2] Department of General Medicine, St. John's Medical College Hospital, Bengaluru, India

Correspondence to: Dr Karuna Rameshkumar, Professor and Head, Department of Clinical Pathology, St. John's Medical College Hospital, Bengaluru-560 034, India.

E-mail: karunark@yahoo.com

Received: 8 June 2010

Accepted in revised form: 13 October 2010
Table 1. Summary of the salient laboratory features and blood
group phenotype

Details                             Parasite species    'A'

Number affected                            Pf           14
                                           Pv           8
Adult                                      Pf           12
                                           Pv           8
Hb range (g%)                              Pf           5.2-15.2
                                           Pv           7.6-13.5
Total WBC count (per [mm.sup.3])           Pf           2300-24,000
                                           Pv           3200-9800
Platelet count (per [mm.sup.3])            Pf           10,000-1.4 lakh
                                           Pv           35,000-1.3 lakh

Details                             'B'               'O'

Number affected                     27                21
                                    15                14
Adult                               23                14
                                    13                7
Hb range (g%)                       6.7-13.9          6.5-14.6
                                    8.9-14.1          7.4-14.4
Total WBC count (per [mm.sup.3])    2900-28,700       3500-11,400
                                    3200-6400         2800-10,000
Platelet count (per [mm.sup.3])     9000-2.6 lakh     13,000-2.8 lakh
                                    29,000-1.7 lakh   13,000-1.7 lakh

Fig. 1: Comparison of O and non-O blood group with clinical
severity. By applying chi-square test, it was observed that
proportion of O group was 76% (26) compared to 24% (8)
in Non-O group which was significant (p<0.05), suggesting
that O group confers. When it was further calculated, the
severity was less in A than in B group.

Cross table

COUNT                      Non-O group   O group

Non-severe malaria         39             27
Severe malaria             26              8

Note: Table made from bar graph.

Severity of                 Blood group     Total
malaria *
                          Non-O Gr   O Gr

Non-severe malaria        39         27      66
Severe malaria            26          8      34

Total                     65         35     100

* Severe malaria is defined as: Hyperparasitaemia >10%
parasitaemia; severe anaemia with Hb <6 g%; clinical signs of
severe malaria with both hepatomegaly, splenomegaly or throm-
bocytopenia

                          Chi-square tests

                          df   Asymp. sig   Exact sig   Exact sig
                               (2-sided)    (2-sided)   (1-sided)

Pearson chi-square        1    0.062
Continuity correlation    1    0.099
Likelihood ratio          1    0.057
Fisher's Exact                              0.080       0.048
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Article Details
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Title Annotation:Research Articles
Author:Deepa; Alwar, Vanamala A.; Rameshkumar, Karuna; Ross, Cecil
Publication:Journal of Vector Borne Diseases
Article Type:Clinical report
Geographic Code:9INDI
Date:Mar 1, 2011
Words:3393
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