Malaria burden and pre-hospital medication among subjects with malaria in Maiduguri, Northeast Nigeria.

The study re-visited malaria burden and pre-hospital medication among malarious subjects in Maiduguri, Northeast Nigeria. A total of 1,657 febrile subjects were screened for malaria by microscopy at two health institutions. Giemsa-stained blood smears were examined for parasitaemia and gametocytaemia; and parasite density (PD), gametocyte density (GD) and gametocyte sex ratio (GSR) were determined. The mean age of the 1,657 subjects was 27.5 ± 12.2 years and 7.8% (130/1,657) of the subjects aged <5 years. Sex distribution showed 47.0% (778/1,657) males and 53.0% (879/1657) females. Parasitaemia was recorded in 22.6% (375/1,657) with geometric mean PD of 8,925 (320-275,000) parasites/µl blood. The prevalence of parasitaemia was highest among subjects <5 years (χ2 = 401.1; df = 5; p < 0.0001) and in August and September (χ2 = 406.9; df = 11; p < 0.0001). Prevalence of gametocytaemia was 12.8% (48/375) with geometric mean GD of 109 (8-464) gametocytes/µl blood. The prevalence was higher in dry (16.5%, 29/176) than wet (9.5%, 19/199) months (χ2 = 4.0; df = 1; p = 0.045). The weighted mean GSR was 0.4 ± 0.1 with highest value in March (0.7 ± 0.2). Pre-hospital medication was recorded in 74.1% (278/375) of the subjects with parasitaemia. Analgesics (51.7%; 194/375) accounted for the highest proportion of drug consumed while 9.3% (35/375) of the subjects took antimalarial drugs. Malaria persisted in Maiduguri especially among subjects <5 years during wet months and pre-hospital medication is a common practice. These findings could serve as guide for policy decision that could contribute to effective treatment and control of malaria in the region.

Impact of comorbidity on adverse drug reaction profile in a cohort of patients treated with Artemisinin combination therapies for uncomplicated malaria in Nigeria.

Artemisinin-based combination antimalarial therapy (ACTs), is still highly effective in uncomplicated falciparum malaria, however, there remain some concerns in relation to its safety and tolerability. Comorbid disease conditions may influence susceptibility to adverse drug reactions (ADRs) as the presence of multiple disease conditions may predisposes patients to ADRs due to the use of many medicines. There is therefore need to assess the impact of comorbidities on the ADR profile of malaria patients treated with ACTs. The study was carried out in health care facilities spread across Nigeria. From the database of over 10,000 patients recruited into an initial cohort, data for 1000 patients with comorbidities was extracted and matched with a control group of 1000 randomly selected patients with no comorbidity. There were 1105 adverse drug reactions in all, of which 66.2% were recorded in patients with comorbidity, and 34% are patients without comorbidity. The mean age of patients with comorbidities was 38.3 ± 17.5 years and 23.8 ± 17.2 for those without comorbidity. Out of the 979 patients with comorbidity, 36% were hypertensive, 2.2% hypertensive-diabetes, 16.4% peptic ulcer disease, 10.4% HIV/AIDS, 4.4% diabetes and 4.3% were asthmatic. Patients with comorbidity were three times more likely to have adverse drug reaction than those without comorbidity (Odds ration = 2.96; 95% CI = 2.23-3.93). HIV/AIDS and osteoarthritis were significantly associated with development of adverse drug reactions. Probability was <0.0001. Age, weight, and height of patients were also found to be risk factor for development of adverse drug reactions.

In vitro sensitivity of Plasmodium falciparum clinical isolates to 4-aminoquinolines in Northeast Nigeria.

Background: Widespread dr ug-resistant Plasmodium falciparum strains have challenged the pivotal role played by 4-aminoquinolines, including chloroquine (CQ), which has been delisted for the treatment of malaria in most parts of the world. This study assessed the in vitro sensitivity of P. falciparum clinical isolates (PfCIs) to amodiaquine (AQ) and CQ in Northeast Nigeria. Materials and methods: PfCIs were collected from subjects with uncomplicated P. falciparum malaria in Azare, Bauchi State and Maiduguri, Borno State following an informed consent. The in vitro sensitivity was assessed by micro-test (MarkIII) method and the IC50 of AQ and CQ was determined using HN-NonLin Version VI.1 software. The reference standard cut-off values for in vitro AQ and CQ resistance of 80 and 160 nmol/l, respectively, were used. Isolates that were inhibited by lower AQ and CQ concentrations were referred to as sensitive. Results: Valid in vitro assay r esults were obtained for 88.9% (80/90) of the PfCIs; Azare had 93.3% (28/30) and Maiduguri had 86.7% (52/60) [χ2 = 0.35; df = 1; p = 0.486]. The geometric mean (GM) IC50 of AQ and CQ were 24.2 nmol/l (95% CI, 10.5 - 49.6 nmol/l) and 39.5 nmol/l (95% CI, 34.5 - 49.6 nmol/l), respectively. The AQ (p = 0.922) and CQ (p = 0.085) GM IC50 were similar between Azare and Maiduguri PfCIs. Only one isolate showed in vitro resistance to AQ giving a sensitivity of 98.8% (79/80) while 17 PfCIs showed in vitro resistance to CQ giving a sensitivity of 78.8% (63/80). The CQ sensitivity was similar between Azare (67.9%; 19/28) and Maiduguri (84.6%; 44/52) PfCIs (χ2 = 3.05; df = 1; p = 0.081). Conclusions: The findings may suggest that the AQ in vitro sensitivity remains high and the isolates in Northeast Nigeria may appear more sensitive to CQ than isolates from other parts. These findings may affect malaria treatment and control policy in Nigeria.

Population structure of Plasmodium falciparum gametocyte sex ratios in malarious children in an endemic area.

The gametocyte sex ratio (proportion of gametocytes that are male) of Plasmodium falciparum may influence transmission. The distribution of P. falciparum sex ratios, the extent of inbreeding, the relationship between clone multiplicity and sex ratio, and the pre- and post-treatment factors influencing a sex ratio of 0.5 were determined in 1609 children, with acute malaria. Gametocytes were sexed by morphological appearance and asexual clone multiplicity was determined by polymerase chain reaction (PCR) using polymorphic loci of merozoite surface proteins-1 and -2 (MSP-1, MSP-2) and glutamine-rich protein (GLURP). The weighted mean population sex ratio on presentation in 162 gametocyte carriers was 0.22, that is, 3.5 female to 1 male (95% CI 0.15-0.28), with an estimated inbreeding rate (f) (the proportion of a mother's daughters that is fertilized by her sons) of 0.56 (95% CI 0.44-0.70). Sex ratio was significantly higher when clone multiplicity was >1 infecting clone than when it was 1 (P=0.02). The frequency of a pre-treatment sex ratio of 0.5 was low (3%), and was significantly increased by non-artemisinin but not by artemisinin - mono or combination - drugs by day 7 after therapy commenced (P=0.03 and P=0.44, respectively). No factor was associated with a pre-treatment sex ratio of 0.5 but two factors were independent predictors of a sex ratio of 0.5 by day 7 after therapy commenced: an age >or=5 years and anaemia. These population data provide some empirical support for the predictions of local mate competition (LMC) theory and, in conjunction with effects of antimalarials on a sex ratio of 0.5, may have implications for malaria control efforts in endemic settings.

Effects of amodiaquine, artesunate, and artesunate-amodiaquine on Plasmodium falciparum malaria-associated anaemia in children.

The effects of amodiaquine, artesunate and artesunate-amodiaquine on Plasmodium falciparum malaria-associated anaemia (PfMAA) and the recovery from PfMAA were evaluated in 328 children with uncomplicated malaria randomized to the standard dose regimens of the three drug treatments. Overall, malaria-attributable fall in haematocrit (MAFH) before treatment was 4.8+/-2.8%, 95% confidence interval (CI) 4.4-5.2%, and was not significantly different between the treatment groups (P=0.31). An age <5 years and a history of illness >3d were independent predictors of MAFH before treatment >4%. Following treatment, drug-attributable fall in haematocrit (DAFH) was significantly higher in amodiaquine-treated children (4.6+/-2.9%, 2.8+/-1.8%, 3.0+/-1.8% for amodiaquine, artesunate, artesunate-amodiaquine, respectively, P<0.0001). The rate of DAFH was significantly lower in artesunate-treated children (1.4+/-0.9%, 0.7+/-0.6%, 1.0+/-0.6% per day for amodiaquine, artesunate and artesunate-amodiaquine, respectively, P<0.0001). The rate of rise in haematocrit from the nadir on days 3-7 was significantly higher in amodiaquine treated children (P=0.045). In anaemic children (n=68), the time elapsing from treatment to the attainment of a haematocrit > or =30%, the anaemia resolution time, and the proportion of anaemic children with complete resolution on day 14 were similar in all treatment groups (P=0.17 and 0.65, respectively). Artemisinin drugs may reduce the extent and rate of fall in PfMAA during treatment and may attenuate malaria-associated anaemia in children.

Plasmodium falciparum gametocyte sex ratios in symptomatic children treated with antimalarial drugs.

The sex ratios of Plasmodium falciparum gametocytes, defined as the proportion of gametocytes in peripheral blood that were male, were evaluated in 1609 children with acute, symptomatic, uncomplicated malaria, pre- and post-treatment with various antimalarial drugs, over an 8-year period (1999-2006) in an endemic area of southwest Nigeria. Gametocyte carriage on presentation was 10% (162 children). In 162 children in whom 5797 gametocytes were sexed on presentation, the weighted mean sex ratio was 0.18 (95% confidence interval 0.13-0.25). Following therapy, in 446 children in whom 38,519 gametocytes were sexed, the weighted mean sex ratio was 0.38 (95% CI 0.33-0.43) on day 3 and 0.70 (95% CI 0.63-0.75) (P<0.000001) by day 7 after therapy commenced. Non-artemisinin monotherapy significantly increased sex ratio producing a male-biased ratio, but artemisinin combination therapy significantly reduced the sex ratio producing a female biased ratio. Pre-treatment sex ratio correlated negatively with haematocrit (r=-0.229, P=0.003) or gametocytaemia (r=-0.435, P<0.0001) but not with other clinical or parasitological parameters. The ratio of the sex-specific half lives male:female, the 'gametocyte maleness index' (GMI), was >1 with non-artemisinin monotherapy but <1 with artesunate and artemisinin-based combinations. In a multiple regression model, anaemia, low gametocytaemia, and enrolment before 2004 were independent predictors of a male-biased sex ratio pre-treatment. A pre-treatment haematocrit <25%, enrolment before 2004 and treatment with non-artemisinin monotherapy were independent predictors of a male-biased sex ratio 7 days postinitiation of therapy. These findings may have implications for malaria management efforts in sub-Saharan Africa.

Some features of primary and recrudescent amodiaquine-resistant Plasmodium falciparum infections in Nigerian children

Characteristics of primary and recrudescent Plasmodium falciparum infections were evaluated in 25 children who did not recover after amodiaquine (AQ) treatment. Recrudescence was detected by a thick blood smear and confirmed by polymerase chain reaction. Over half of recrudescent events occurred after 14 days of initiation of treatment and were associated with relatively low asexual parasitaemia. We examined the gametocyte sex ratio (GSR) in these children and in age and gender-matched controls that had AQ-sensitive (AQ-S) infections (n = 50). In both AQ-S and AQ-resistant (AQ-R) infections, the GSR was female-biased pre-treatment and became male-biased by the third day after treatment initiation. However, gametocyte males persisted after this period in children with AQ-R infections. AQ-recrudescent infections are relatively low (25 of 612.4 percent) in children from this endemic area.

Plasmodium falciparum gametocyte sex ratios in children with acute, symptomatic, uncomplicated infections treated with amodiaquine.

BACKGROUND: Amodiaquine is frequently used as a partner drug in combination therapy or in some setting as monotherapy, but little is known about its effects on gametocyte production and sex ratio and its potential influence on transmission in Africa. The effects of amodiaquine on sexual stage parasites and gametocyte sex ratio, and the factors associated with a male-biased sex ratio were evaluated in 612 children with uncomplicated Plasmodium falciparum malaria who were treated with amodiaquine during the period 2000 - 2006 in an endemic area. METHODS: Clinical, parasitological and laboratory parameters were evaluated before treatment and during follow-up for 28-42 days, and according to standard methods. Gametocyte sex ratio was defined as the proportion of peripheral gametocytes that are male. RESULTS: Clinical recovery from illness occurred in all children. Gametocytaemia was detected in 66 patients (11%) before treatment and in another 56 patients (9%) after treatment. Gametocyte densities were significantly higher by days 3-7 following treatment compared with pre-treatment (P < 0.0001). Overall, mean gametocyte sex ratio increased significantly during follow-up and over the study periods from 2000-2006 (P < 0.001 in both cases), but was female-biased at enrolment throughout the study periods. Absence of fever, a haematocrit < 25%, asexual parasitaemia > 20,000/microL, gametocytaemia < 18/microL, and enrolment in 2006 were associated with a male-biased sex ratio pre-treatment. Anaemia and high parasitaemia were independent predictors of gametocyte maleness 7 days post treatment. CONCLUSION: Amodiaquine may significantly increase gametocyte carriage, density and sex ratio, and may potentially influence transmission. It is possible that anaemia could have contributed to the increased sex ratio. These findings may have implications for malaria control efforts in Africa.

Some features of primary and recrudescent amodiaquine-resistant Plasmodium falciparum infections in Nigerian children.

Characteristics of primary and recrudescent Plasmodium falciparum infections were evaluated in 25 children who did not recover after amodiaquine (AQ) treatment. Recrudescence was detected by a thick blood smear and confirmed by polymerase chain reaction. Over half of recrudescent events occurred after 14 days of initiation of treatment and were associated with relatively low asexual parasitaemia. We examined the gametocyte sex ratio (GSR) in these children and in age and gender-matched controls that had AQ-sensitive (AQ-S) infections (n = 50). In both AQ-S and AQ-resistant (AQ-R) infections, the GSR was female-biased pre-treatment and became male-biased by the third day after treatment initiation. However, gametocyte males persisted after this period in children with AQ-R infections. AQ-recrudescent infections are relatively low (25 of 612.4%) in children from this endemic area.