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  • 51. Mukanga, David
    et al.
    Tibenderana, James K.
    Peterson, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH).
    Pariyo, George W.
    Kiguli, Juliet
    Waiswa, Peter
    Babirye, Rebecca
    Ojiambo, Godfrey
    Kasasa, Simon
    Pagnoni, Franco
    Kallander, Karin
    Access, acceptability and utilization of community health workers using diagnostics for case management of fever in Ugandan children: a cross-sectional study2012In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 11, p. 121-Article in journal (Refereed)
    Abstract [en]

    Background: Use of diagnostics in integrated community case management (iCCM) of fever is recognized as an important step in improving rational use of drugs and quality of care for febrile under-five children. This study assessed household access, acceptability and utilization of community health workers (CHWs) trained and provided with malaria rapid diagnostic tests (RDTs) and respiratory rate timers (RRTs) to practice iCCM.

    Methods: A total of 423 households with under-five children were enrolled into the study in Iganga district, Uganda. Households were selected from seven villages in Namungalwe sub-county using probability proportionate to size sampling. A semi-structured questionnaire was administered to caregivers in selected households. Data were entered into Epidata statistical software, and analysed using SPSS Statistics 17.0, and STATA version 10.

    Results: Most (86%, 365/423) households resided within a kilometre of a CHW's home, compared to 26% (111/423) residing within 1 km of a health facility (p<0.001). The median walking time by caregivers to a CHW was 10 minutes (IQR 5-20). The first option for care for febrile children in the month preceding the survey was CHWs (40%, 242/601), followed by drug shops (33%, 196/601). Fifty-seven percent (243/423) of caregivers took their febrile children to a CHW at least once in the three month period preceding the survey. Households located 1-3 km from a health facility were 72% (AOR 1.72; 95% CI 1.11-2.68) more likely to utilize CHW services compared to households within 1 km of a health facility. Households located 1-3 km from a CHW were 81% (AOR 0.19; 95% CI 0.10-0.36) less likely to utilize CHW services compared to those households residing within 1 km of a CHW. A majority (79%, 336/423) of respondents thought CHWs services were better with RDTs, and 89% (375/423) approved CHWs' continued use of RDTs. Eighty-six percent (209/243) of respondents who visited a CHW thought RRTs were useful.

    Conclusion: ICCM with diagnostics is acceptable, increases access, and is the first choice for caregivers of febrile children. More than half of caregivers of febrile children utilized CHW services over a three-month period. However, one-third of caregivers used drug shops in spite of the presence of CHWs.

  • 52.
    Mwaiswelo, Richard
    et al.
    Muhimbili Univ Hlth & Allied Sci, Dept Parasitol & Med Entomol, Dar Es Salaam, Tanzania..
    Ngasala, Billy E.
    Muhimbili Univ Hlth & Allied Sci, Dept Parasitol & Med Entomol, Dar Es Salaam, Tanzania..
    Jovel, Irina
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden..
    Gosling, Roland
    Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA.;Univ Calif San Francisco, Global Hlth Grp, San Francisco, CA 94143 USA..
    Premji, Zul
    Aga Khan Univ Hosp, Nairobi, Kenya..
    Poirot, Eugenie
    Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA.;Univ Calif San Francisco, Global Hlth Grp, San Francisco, CA 94143 USA..
    Mmbando, Bruno P.
    Tanga Ctr, Natl Inst Med Res, Tanga, Tanzania..
    Bjorkman, Anders
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden..
    Mårtensson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH).
    Safety of a single low-dose of primaquine in addition to standard artemether-lumefantrine regimen for treatment of acute uncomplicated Plasmodium falciparum malaria in Tanzania2016In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 15, article id 316Article in journal (Refereed)
    Abstract [en]

    Background: This study assessed the safety of the new World Health Organization (WHO) recommendation of adding a single low-dose of primaquine (PQ) to standard artemisinin-based combination therapy (ACT), regardless of individual glucose-6-phosphate dehydrogenase (G6PD) status, for treatment of acute uncomplicated Plasmodium falciparum malaria in Tanzania. Methods: Men and non-pregnant, non-lactating women aged >= 1 year with uncomplicated P. falciparum malaria were enrolled and randomized to either standard artemether-lumefantrine (AL) regimen alone or with a 0.25 mg/kg single-dose of PQ. PQ was administered concomitantly with the first AL dose. All drug doses were supervised. Safety was evaluated between days 0 and 28. G6PD status was assessed using rapid test (CareStart (TM)) and molecular genotyping. The primary endpoint was mean percentage relative reduction in haemoglobin (Hb) concentration (g/dL) between days 0 and 7 by genotypic G6PD status and treatment arm. Results: Overall, 220 patients, 110 per treatment arm, were enrolled, of whom 33/217 (15.2 %) were phenotypically G6PD deficient, whereas 15/110 (13.6 %) were genotypically hemizygous males, 5/110 (4.5 %) homozygous females and 22/110 (20 %) heterozygous females. Compared to genotypically G6PD wild-type/normal [ 6.8, 95 % confidence interval (CI) 4.67-8.96], only heterozygous patients in AL arm had significant reduction in day-7 mean relative Hb concentration (14.3, 95 % CI 7.02-21.55, p=0.045), however, none fulfilled the pre-defined haemolytic threshold value of >= 25 % Hb reduction. After adjustment for baseline parasitaemia, Hb, age and sex the mean relative Hb reduction was not statistically significant in both heterozygous and hemizygous/homozygous patients in both arms. A majority of the adverse events (AEs) were mild and unrelated to the study drugs. However, six (4.4 %) episodes, three per treatment arm, of acute haemolytic anaemia occurred between days 0 and 7. Three occurred in phenotypically G6PD deficient patients, two in AL and one in AL + PQ arm, but none in genotypically hemizygous/homozygous patients. All patients with acute haemolytic anaemia recovered without medical intervention. Conclusion: The findings support that the WHO recommendation of adding a single low-dose of PQ to standard AL regimen is safe for the treatment of acute uncomplicated P. falciparum malaria regardless of G6PD status in Tanzania.

  • 53.
    Mwaiswelo, Richard
    et al.
    Muhimbili Univ Hlth & Allied Sci, Dept Parasitol & Med Entomol, Dar Es Salaam, Tanzania..
    Ngasala, Billy
    Muhimbili Univ Hlth & Allied Sci, Dept Parasitol & Med Entomol, Dar Es Salaam, Tanzania..
    Jovel, Irina
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden..
    Aydin-Schmidt, Berit
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden..
    Gosling, Roland
    Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA.;Univ Calif San Francisco, Global Hlth Grp, San Francisco, CA 94143 USA..
    Premji, Zul
    Aga Khan Univ Hosp, Nairobi, Kenya..
    Mmbando, Bruno
    Natl Inst Med Res, Tanga Ctr, Tanga, Tanzania..
    Bjorkman, Anders
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden..
    Mårtensson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH).
    Adding a single low-dose of primaquine (0.25 mg/kg) to artemether-lumefantrine did not compromise treatment outcome of uncomplicated Plasmodium falciparum malaria in Tanzania: a randomized, single-blinded clinical trial2016In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 15, article id 435Article in journal (Refereed)
    Abstract [en]

    Background: The World Health Organization (WHO) recently recommended the addition of a single low-dose of the gametocytocidal drug primaquine (PQ) to artemisinin-based combination therapy (ACT) in low transmission settings as a component of pre-elimination or elimination programmes. However, it is unclear whether that influences the ACT cure rate. The study assessed treatment outcome of artemether-lumefantrine (AL) plus a single PQ dose (0.25 mg/kg) versus standard AL regimen for treatment of acute uncomplicated Plasmodium falciparum malaria in Tanzania. Methods: A randomized, single-blinded, clinical trial was conducted in Yombo, Bagamoyo district, Tanzania. Acute uncomplicated P. falciparum malaria patients aged >= 1 year, with the exception of pregnant and lactating women, were enrolled and treated with AL plus a single PQ dose (0.25 mg/kg) or AL alone under supervision. PQ was administered together with the first AL dose. Clinical and laboratory assessments were performed at 0, 8, 24, 36, 48, 60, and 72 h and on days 7, 14, 21, and 28. The primary end-point was a polymerase chain reaction (PCR)-adjusted adequate clinical and parasitological response (ACPR) on day 28. Secondary outcomes included: fever and asexual parasitaemia clearance, proportion of patients with PCR-determined parasitaemia on day 3, and proportion of patients with Pfmdr1 N86Y and Pfcrt K76T on days 0, 3 and day of recurrent infection. Results: Overall 220 patients were enrolled, 110 were allocated AL + PQ and AL, respectively. Parasite clearance by microscopy was fast, but PCR detectable parasitaemia on day 3 was 31/109 (28.4 %) and 29/108 (26.9 %) in patients treated with AL + PQ and AL, respectively (p = 0.79). Day 28 PCR-adjusted ACPR and re-infection rate was 105/105 (100 %) and 101/102 (99 %) (p = 0.31), and 5/107 (4.7 %) and 5/8 (4.8 %) (p = 0.95), in AL + PQ and AL arm, respectively. There was neither any statistically significant difference in the proportion of Pfmdr1 N86Y or Pfcrt K76T between treatment arms on days 0, 3 and day of recurrent infection, nor within treatment arms between days 0 and 3 or day 0 and day of recurrent infection. Conclusion: The new WHO recommendation of adding a single low-dose of PQ to AL did not compromise treatment outcome of uncomplicated P. falciparum malaria in Tanzania.

  • 54. Nasr, Amre
    et al.
    Iriemenam, Nnaemeka C.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Giha, Hayder
    Balogun, Halima A.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Anders, Robin F.
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    ElGhazali, Gehad
    Berzins, Klavs
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    FcgammaRIIa (CD32) polymorphism and anti-malarial IgG subclass pattern among Fulani and sympatric ethnic groups living in eastern Sudan2009In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 8, no 43, p. 1-10Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: A SNP at position 131, in the FcgammaRIIa gene, affects the binding of the different IgG subclasses and may influence the clinical variation seen in patients with falciparum malaria. This study confirms and extends previous findings, analysing the FcgammaRIIa (CD32) polymorphism in relation to the IgG subclass distribution seen among two sympatric tribes living in eastern Sudan, characterized by marked differences in susceptibility to Plasmodium falciparum malaria. METHODS: Two hundred and fifty Fulani subjects living in an area of meso-endemic P. falciparum malaria infection were genotyped for the FcgammaRIIa-131 polymorphism. For comparison, 101 non-Fulani donors - (Masaleit, Hausa and Four) - living in the same study area, were genotyped. The levels of plasma antibodies (IgG and subclasses) to four malaria antigens (AMA-1, MSP 2 - 3D7 & FC27, Pf332-C231) were measured using indirect enzyme-linked immunosorbent assays. RESULTS: The FcgammaRIIa-H/H131 genotype was found to be significantly more prevalent in the Fulani as compared to the non-Fulani ethnic groups (36.0% for Fulani versus 17.8% for non-Fulani, adjusted OR 3.10, 95% CI 1.61-5.97, P value < 0.001). The Fulani showed lower anti-malarial IgG1 and IgG3 antibody levels as compared to the non-Fulani and higher levels of IgG2 antibodies. CONCLUSION: The FcgammaRIIa-H/H131 genotype and H131 allele is at higher frequency in the Fulani ethnic group. The H/H131 genotype was consistently associated with higher levels of anti-malarial IgG2 and IgG3 antibodies, while the R/R131 genotype was associated with higher levels of IgG1 antibodies.

  • 55. Ngasala, Billy E.
    et al.
    Malmberg, Maja
    Carlsson, Anja M.
    Ferreira, Pedro E.
    Petzold, Max G.
    Blessborn, Daniel
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    Bergqvist, Yngve
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    Gil, Jose P.
    Premji, Zul
    Martensson, Andreas
    Effectiveness of artemether-lumefantrine provided by community health workers in under-five children with uncomplicated malaria in rural Tanzania: an open label prospective study2011In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 10, article id 64Article in journal (Refereed)
    Abstract [en]

    Background: Home-management of malaria (HMM) strategy improves early access of anti-malarial medicines to high-risk groups in remote areas of sub-Saharan Africa. However, limited data are available on the effectiveness of using artemisinin-based combination therapy (ACT) within the HMM strategy. The aim of this study was to assess the effectiveness of artemether-lumefantrine (AL), presently the most favoured ACT in Africa, in under-five children with uncomplicated Plasmodium falciparum malaria in Tanzania, when provided by community health workers (CHWs) and administered unsupervised by parents or guardians at home.

    Methods: An open label, single arm prospective study was conducted in two rural villages with high malaria transmission in Kibaha District, Tanzania. Children presenting to CHWs with uncomplicated fever and a positive rapid malaria diagnostic test (RDT) were provisionally enrolled and provided AL for unsupervised treatment at home. Patients with microscopy confirmed P. falciparum parasitaemia were definitely enrolled and reviewed weekly by the CHWs during 42 days. Primary outcome measure was PCR corrected parasitological cure rate by day 42, as estimated by Kaplan-Meier survival analysis. This trial is registered with ClinicalTrials.gov, number NCT00454961.

    Results: A total of 244 febrile children were enrolled between March-August 2007. Two patients were lost to follow up on day 14, and one patient withdrew consent on day 21. Some 141/241 (58.5%) patients had recurrent infection during follow-up, of whom 14 had recrudescence. The PCR corrected cure rate by day 42 was 93.0% (95% CI 88.3%-95.9%). The median lumefantrine concentration was statistically significantly lower in patients with recrudescence (97 ng/mL [IQR 0-234]; n = 10) compared with reinfections (205 ng/mL [114-390]; n = 92), or no parasite reappearance (217 [121-374] ng/mL; n = 70; p <= 0.046).

    Conclusions: Provision of AL by CHWs for unsupervised malaria treatment at home was highly effective, which provides evidence base for scaling-up implementation of HMM with AL in Tanzania.

  • 56. Ngasala, Billy E.
    et al.
    Malmberg, Maja
    Carlsson, Anja M.
    Ferreira, Pedro E.
    Petzold, Max G.
    Blessborn, Daniel
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry.
    Bergqvist, Yngve
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry, Analytical Chemistry.
    Gil, Jose P.
    Premji, Zul
    Mårtensson, Andreas
    Effectiveness of artemether-lumefantrine provided by community health workers in under-five children with uncomplicated malaria in rural Tanzania: an open label prospective study2011In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 10, p. 64-Article in journal (Refereed)
    Abstract [en]

    Background: Home-management of malaria (HMM) strategy improves early access of anti-malarial medicines to high-risk groups in remote areas of sub-Saharan Africa. However, limited data are available on the effectiveness of using artemisinin-based combination therapy (ACT) within the HMM strategy. The aim of this study was to assess the effectiveness of artemether-lumefantrine (AL), presently the most favoured ACT in Africa, in under-five children with uncomplicated Plasmodium falciparum malaria in Tanzania, when provided by community health workers (CHWs) and administered unsupervised by parents or guardians at home. Methods: An open label, single arm prospective study was conducted in two rural villages with high malaria transmission in Kibaha District, Tanzania. Children presenting to CHWs with uncomplicated fever and a positive rapid malaria diagnostic test (RDT) were provisionally enrolled and provided AL for unsupervised treatment at home. Patients with microscopy confirmed P. falciparum parasitaemia were definitely enrolled and reviewed weekly by the CHWs during 42 days. Primary outcome measure was PCR corrected parasitological cure rate by day 42, as estimated by Kaplan-Meier survival analysis. This trial is registered with ClinicalTrials.gov, number NCT00454961. Results: A total of 244 febrile children were enrolled between March-August 2007. Two patients were lost to follow up on day 14, and one patient withdrew consent on day 21. Some 141/241 (58.5%) patients had recurrent infection during follow-up, of whom 14 had recrudescence. The PCR corrected cure rate by day 42 was 93.0% (95% CI 88.3%-95.9%). The median lumefantrine concentration was statistically significantly lower in patients with recrudescence (97 ng/mL [IQR 0-234]; n = 10) compared with reinfections (205 ng/mL [114-390]; n = 92), or no parasite reappearance (217 [121-374] ng/mL; n = 70; p <= 0.046). Conclusions: Provision of AL by CHWs for unsupervised malaria treatment at home was highly effective, which provides evidence base for scaling-up implementation of HMM with AL in Tanzania.

  • 57. Okafor, Christian M. F.
    et al.
    Anumudu, Chiaka I.
    Omosun, Yusuf O.
    Uthaipibull, Chairat
    Ayede, Idowu
    Awobode, Henrietta O.
    Odaibo, Alex B.
    Langhorne, Jean
    Holder, Anthony A.
    Nwuba, Roseangela I.
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Cellular responses to modified Plasmodium falciparum MSP1(19) antigens in individuals previously exposed to natural malaria infection2009In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 8, p. 263-Article in journal (Refereed)
    Abstract [en]

    Background: MSP1 processing-inhibitory antibodies bind to epitopes on the 19 kDa C-terminal region of the Plasmodium falciparum merozoite surface protein 1 (MSP1(19)), inhibiting erythrocyte invasion. Blocking antibodies also bind to this antigen but prevent inhibitory antibodies binding, allowing invasion to proceed. Recombinant MSP1(19) had been modified previously to allow inhibitory but not blocking antibodies to continue to bind. Immunization with these modified proteins, therefore, has the potential to induce more effective protective antibodies. However, it was unclear whether the modification of MSP1(19) would affect critical T-cell responses to epitopes in this antigen. Methods: The cellular responses to wild-type MSP1(19) and a panel of modified MSP1(19) antigens were measured using an in-vitro assay for two groups of individuals: the first were malaria-nave and the second had been naturally exposed to Plasmodium falciparum infection. The cellular responses to the modified proteins were examined using cells from malaria-exposed infants and adults. Results: Interestingly, stimulation indices (SI) for responses induced by some of the modified proteins were at least two-fold higher than those elicited by the wild-type MSP1(19). A protein with four amino acid substitutions (Glu27 -> Tyr, Leu31 -> Arg, Tyr34 -> Ser and Glu43 -> Leu) had the highest stimulation index (SI up to 360) and induced large responses in 64% of the samples that had significant cellular responses to the modified proteins. Conclusion: This study suggests that specific MSP1(19) variants that have been engineered to improve their antigenicity for inhibitory antibodies, retain T-cell epitopes and the ability to induce cellular responses. These proteins are candidates for the development of MSP1-based malaria vaccines.

  • 58. Okal, Michael N.
    et al.
    Lindh, Jenny M.
    KTH, School of Chemical Science and Engineering (CHE), Chemistry, Organic Chemistry.
    Torr, Steve J.
    Masinde, Elizabeth
    Orindi, Benedict
    Lindsay, Steve W.
    Fillinger, Ulrike
    Analysing the oviposition behaviour of malaria mosquitoes: design considerations for improving two-choice egg count experiments2015In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 14, article id 250Article in journal (Refereed)
    Abstract [en]

    Background: Choice egg-count bioassays are a popular tool for analysing oviposition substrate preferences of gravid mosquitoes. This study aimed at improving the design of two-choice experiments for measuring oviposition substrates preferences of the malaria vector Anopheles gambiae senso lato, a mosquito that lays single eggs. Methods: In order to achieve high egg-laying success of female An. gambiae sensu stricto (s.s.) and Anopheles arabiensis mosquitoes in experiments, four factors were evaluated: (1) the time provided for mating; (2) the impact of cage size, mosquito age and female body size on insemination; (3) the peak oviposition time; and, (4) the host sources of blood meal. Choice bioassays, with one mosquito released in each cage containing two oviposition cups both with the same oviposition substrate (100 ml water), were used to measure and adjust for egg-laying characteristics of the species. Based on these characteristics an improved design for the egg-count bioassay is proposed. Results: High oviposition rates [84%, 95% confidence interval (CI) 77-89%] were achieved when 300 male and 300 blood-fed female An. gambiae s.s. were held together in a cage for 4 days. The chances for oviposition dropped (odds ratio 0.30; 95% CI 0.14-0.66) when human host source of blood meal was substituted with a rabbit but egg numbers per female were not affected. The number of eggs laid by individual mosquitoes was overdispersed (median = 52, eggs, interquartile range 1-214) and the numbers of eggs laid differed widely between replicates, leading to a highly heterogeneous variance between groups and/or rounds of experiments. Moreover, one-third of mosquitoes laid eggs unequally in both cups with similar substrates giving the illusion of choice. Sample size estimations illustrate that it takes 165 individual mosquitoes to power bioassays sufficiently (power = 0.8, p = 0.05) to detect a 15% shift in comparative preferences of two treatments. Conclusion: Two-choice egg count bioassays with Anopheles are best done with a two-tier design that (1) implements a parallel series of experiments with mosquitoes given a choice of two identical substrates choices and, (2) uses a single mosquito in each test cage rather than groups of mosquitoes to assess the preference of a test or control solution. This approach, with sufficient replication, lowers the risk detecting pseudopreferences.

  • 59.
    Pathak, Ashish
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Mårtensson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD).
    Gawariker, Sudhir
    Department of Medicine, R D Gardi Medical College, Surasa, Ujjain, India.
    Mandliya, Jagdish
    Department of Pediatrics, R D Gardi Medical College, Surasa, Ujjain, India.
    Sharma, Ashish
    Department of Medicine, R D Gardi Medical College, Surasa, Ujjain, India.
    Diwan, Vishal
    Department of Public Health Sciences (Global Health/IHCAR), Karolinska Institutet, Stockholm, Sweden.
    Ursing, Johan
    Malaria Research, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
    Characterization of drug resistance associated genetic polymorphisms among Plasmodium falciparum field isolates in Ujjain, Madhya Pradesh, India.2014In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 13, p. 182-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Since 2011, artesunate + sulphadoxine-pyrimethamine (ASP), instead of chloroquine, has been recommended for treatment of uncomplicated malaria in India. In Ujjain, central India, with an annual parasite index <0.1, the prevalence of drug-resistant Plasmodium falciparum is unknown. In other parts of India chloroquine and sulphadoxine-pyrimethamine-resistant P. falciparum is prevalent. The aim of this study was to determine the prevalence of anti-malarial drug resistance-associated genetic polymorphisms in P. falciparum collected in Ujjain in 2009 and 2010, prior to the introduction of ASP.

    METHODS: Blood samples from 87 patients with P. falciparum mono-infection verified by microscopy were collected on filter-paper at all nine major pathology laboratories in Ujjain city. Codons Pfcrt 72-76, pfmdr1 1034-1246, pfdhfr 16-185, pfdhps 436-632 and pfnhe1 ms4760 haplotypes were identified by sequencing. Pfcrt K76T and pfmdr1 N86Y were identified by restriction fragment length polymorphism, and pfmdr1 gene copy number by real-time PCR.

    RESULTS: Sulphadoxine-pyrimethamine resistance-associated pfdhfr 108 N and 59R alleles were found in 75/78 (96%) and 70/78 (90%) samples, respectively, and pfdhps 437G was found in 7/77 (9%) samples. Double mutant pfdhfr 59R + 108 N were found in 62/76 (82%) samples. Triple mutant pfdhfr 59R + 108 N and pfdhps 437G were found in 6/76 (8%) samples. Chloroquine-resistance-associated pfcrt 76 T was found in 82/87 (94%). The pfcrt 72-76 haplotypes found were: 80/84 (95%) SVMNT, 3/84 (4%) CVMNK and 1/84 (1%) CVMNT. Pfmdr1 N86 and 86Y were identified in 70/83 (84%) and 13/83 (16%) samples, respectively. Pfmdr1 S1034 + N1042 + D1246 were identified together in 70/72 (97%) of successfully sequenced samples. One pfmdr1 gene copy was found in 74/75 (99%) successfully amplified samples.

    CONCLUSION: This is the first characterization of key anti-malarial drug resistance-associated genetic markers among P. falciparum collected in Ujjain, Madhya Pradesh, India. The results indicate that the efficacy of standard dose chloroquine at the time of the study was likely to be poor, whereas ASP was likely to be efficacious, supporting the changed drug treatment policy. However, P. falciparum with reduced susceptibility to sulphadoxine-pyrimethamine is highly prevalent, highlighting the need for continuous surveillance of ASP efficacy in the study area.

  • 60.
    Perdijk, Olaf
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Wageningen University, Netherlands.
    Arama, Charles
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. University of Bamako, Mali.
    Giusti, Pablo
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Maiga, Bakary
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. University of Bamako, Mali.
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Dolo, Amagana
    Doumbo, Ogobara
    Persson, Jan-Olov
    Stockholm University, Faculty of Science, Department of Mathematics.
    Boström, Stephanie
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Haptoglobin phenotype prevalence and cytokine profiles during Plasmodium falciparum infection in Dogon and Fulani ethnic groups living in Mali2013In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 12, p. 432-Article in journal (Refereed)
    Abstract [en]

    Background: The Fulani are known to have a lower parasitaemia and less clinical episodes of malaria as compared to the Dogon sympatric ethnic group, living in Mali. Higher circulating malaria-specific antibody titers and increased pro-inflammatory cytokine levels have been shown in Fulani individuals. Several studies have tried to link haptoglobin (Hp) phenotypes with susceptibility to malaria, but without consensus. This study investigated the role of Hp phenotypes and cytokine levels in Dogon and Fulani during asymptomatic Plasmodium falciparum infection. Methods: Two different cohorts were combined in this study: a 2008 cohort with 77 children aged between two and ten years and a 2001 cohort, with 82 children and adults, aged between 11 and 68 years. Hp phenotypes in plasma were measured by Western Blot. Circulating levels of sCD163, IL-6, IL-10, IFN-gamma and TNF were measured by ELISA. Multiple regression analysis was performed to associate Hp phenotypes with cytokine profiles. In addition, in vitro stimulation of peripheral blood mononuclear cells (PBMCs) with Hp:Hb complexes was performed and cytokine release in corresponding supernatants were measured using cytometric bead array. Results: The results revealed a higher Hp2-2 phenotype prevalence in the Fulani. The Hp2-2 phenotype was associated with a higher susceptibility to P. falciparum infection in Dogon, but not in Fulani. In concordance with previous studies, Fulani showed increased inflammatory mediators (IL-6, IFN-gamma) and additionally also increased sCD163 levels compared to Dogon, irrespective of infection. Furthermore, infected individuals showed elevated sCD163 levels compared to uninfected individuals, in both Fulani and Dogon. Multiple regression analysis revealed that the Hp1-1 phenotype was associated with higher levels of TNF and IFN-gamma, as compared to the Hp2-2 phenotype. In vitro stimulation of PBMCs with Hb:Hp1-1 complexes resulted in a pro-inflammatory cytokine profile, whilst stimulation with Hb: Hp2-2 complexes showed a more balanced profile. Conclusions: Ethnicity might be an important confounder on the Hp phenotype-dependent susceptibility to malaria and future studies could consider taking this into account when designing new immunological studies. Although, the relatively small sample size used in this study warrens for precautions in the interpretation of the data and these findings should ideally be validated in a bigger cohort.

  • 61. Portugal, Silvia
    et al.
    Doumtabe, Didier
    Traore, Boubacar
    Miller, Louis H.
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Doumbo, Ogobara K.
    Dolo, Amagana
    Pierce, Susan K.
    Crompton, Peter D.
    B cell analysis of ethnic groups in Mali with differential susceptibility to malaria2012In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 11, p. 162-Article in journal (Refereed)
    Abstract [en]

    Background: Several studies indicate that people of the Fulani ethnic group are less susceptible to malaria compared to those of other ethnic groups living sympatrically in Africa, including the Dogon ethnic group. Although the mechanisms of this protection remain unclear, the Fulani are known to have higher levels of Plasmodium falciparum-specific antibodies of all Ig classes as compared to the Dogon. However, the proportions of B cell subsets in the Fulani and Dogon that may account for differences in the levels of Ig have not been characterized. Methods: In this cross-sectional study, venous blood was collected from asymptomatic Fulani (n = 25) and Dogon (n = 25) adults in Mali during the malaria season, and from P. falciparum-naive adults in the U. S. (n = 8). At the time of the blood collection, P. falciparum infection was detected by blood-smear in 16% of the Fulani and 36% of the Dogon volunteers. Thawed lymphocytes were analysed by flow cytometry to quantify B cell subsets, including immature and naive B cells; plasma cells; and classical, activated, and atypical memory B cells (MBCs). Results: The overall distribution of B cell subsets was similar between Fulani and Dogon adults, although the percentage of activated MBCs was higher in the Fulani group (Fulani: 11.07% [95% CI: 9.317 - 12.82]; Dogon: 8.31% [95% CI: 6.378 - 10.23]; P = 0.016). The percentage of atypical MBCs was similar between Fulani and Dogon adults (Fulani: 28.3% [95% CI: 22.73 - 34.88]; Dogon: 29.3% [95% CI: 25.06 - 33.55], but higher than U. S. adults (U. S.: 3.0% [95% CI: -0.21 - 6.164]; P < 0.001). Plasmodium falciparum infection was associated with a higher percentage of plasma cells among Fulani (Fulani infected: 3.3% [95% CI: 1.788 - 4.744]; Fulani uninfected: 1.71% [95% CI: 1.33 - 2.08]; P = 0.011), but not Dogon adults. Conclusion: These data show that the malaria-resistant Fulani have a higher percentage of activated MBCs compared to the Dogon, and that P. falciparum infection is associated with a higher percentage of plasma cells in the Fulani compared to the Dogon, findings that may account for the higher levels of P. falciparum antibodies in the Fulani.

  • 62.
    Reuterswärd, Philippa
    et al.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Bergström, Sofia
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science.
    Orikiiriza, Judy
    Makerere Univ, Coll Hlth Sci, Infect Dis Inst, Kampala, Uganda..
    Lindquist, Elisabeth
    Umeå Univ, Dept Mol Biol, Umeå, Sweden..
    Bergström, Sven
    Umeå Univ, Dept Mol Biol, Umeå, Sweden..
    Svahn Andersson, Helene
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Ayoglu, Burcu
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science.
    Uhlén, Mathias
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science.
    Wahlgren, Mats
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden..
    Normark, Johan
    Umeå Univ, Dept Mol Biol, Umeå, Sweden..
    Ribacke, Ulf
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden..
    Nilsson, Peter
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science.
    Levels of human proteins in plasma associated with acute paediatric malaria2018In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 17, article id 426Article in journal (Refereed)
    Abstract [en]

    Background: The intimate interaction between the pathophysiology of the human host and the biology of the Plasmodium falciparum parasite results in a wide spectrum of disease outcomes in malaria. Development of severe disease is associated with a progressively augmented imbalance in pro- and anti-inflammatory responses to high parasite loads and sequestration of parasitized erythrocytes. Although these phenomena collectively constitute common denominators for the wide variety of discrete severe malaria manifestations, the mechanistic rationales behind discrepancies in outcome are poorly understood. Exploration of the human pathophysiological response by variations in protein profiles in plasma presents an excellent opportunity to increase the understanding. This is ultimately required for better prediction, prevention and treatment of malaria, which is essential for ongoing elimination and eradication efforts. Results: An affinity proteomics approach was used to analyse 541 paediatric plasma samples collected from community controls and patients with mild or severe malaria in Rwanda. Protein profiles were generated with an antibody-based suspension bead array containing 255 antibodies targetting 115 human proteins. Here, 57 proteins were identified with significantly altered levels (adjusted p-values<0.001) in patients with malaria compared to controls. From these, the 27 most significant proteins (adjusted p-values<10(-14)) were selected for a stringent analysis approach. Here, 24 proteins showed elevated levels in malaria patients and included proteins involved in acute inflammatory response as well as cell adhesion. The remaining three proteins, also implicated in immune regulation and cellular adhesivity, displayed lower abundance in malaria patients. In addition, 37 proteins (adjusted p-values<0.05) were identified with increased levels in patients with severe compared to mild malaria. This set includes, proteins involved in tissue remodelling and erythrocyte membrane proteins. Collectively, this approach has been successfully used to identify proteins both with known and unknown association with different stages of malaria. Conclusion: In this study, a high-throughput affinity proteomics approach was used to find protein profiles in plasma linked to P. falciparum infection and malaria disease progression. The proteins presented herein are mainly involved in inflammatory response, cellular adhesion and as constituents of erythrocyte membrane. These findings have a great potential to provide increased conceptual understanding of host-parasite interaction and malaria pathogenesis.

  • 63. Reuterswärd, Philippa
    et al.
    Bergström, Sofia
    Orikiiriza, Judy
    Lindquist, Elisabeth
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Svahn, Helene Andersson
    Ayoglu, Burcu
    Uhlén, Mathias
    Wahlgren, Mats
    Normark, Johan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Ribacke, Ulf
    Nilsson, Peter
    Levels of human proteins in plasma associated with acute paediatric malaria2018In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 17, article id 426Article in journal (Refereed)
    Abstract [en]

    Background: The intimate interaction between the pathophysiology of the human host and the biology of the Plasmodium falciparum parasite results in a wide spectrum of disease outcomes in malaria. Development of severe disease is associated with a progressively augmented imbalance in pro- and anti-inflammatory responses to high parasite loads and sequestration of parasitized erythrocytes. Although these phenomena collectively constitute common denominators for the wide variety of discrete severe malaria manifestations, the mechanistic rationales behind discrepancies in outcome are poorly understood. Exploration of the human pathophysiological response by variations in protein profiles in plasma presents an excellent opportunity to increase the understanding. This is ultimately required for better prediction, prevention and treatment of malaria, which is essential for ongoing elimination and eradication efforts.

    Results: An affinity proteomics approach was used to analyse 541 paediatric plasma samples collected from community controls and patients with mild or severe malaria in Rwanda. Protein profiles were generated with an antibody-based suspension bead array containing 255 antibodies targetting 115 human proteins. Here, 57 proteins were identified with significantly altered levels (adjusted p-values < 0.001) in patients with malaria compared to controls. From these, the 27 most significant proteins (adjusted p-values < 10−14) were selected for a stringent analysis approach. Here, 24 proteins showed elevated levels in malaria patients and included proteins involved in acute inflammatory response as well as cell adhesion. The remaining three proteins, also implicated in immune regulation and cellular adhesivity, displayed lower abundance in malaria patients. In addition, 37 proteins (adjusted p-values < 0.05) were identified with increased levels in patients with severe compared to mild malaria. This set includes, proteins involved in tissue remodelling and erythrocyte membrane proteins. Collectively, this approach has been successfully used to identify proteins both with known and unknown association with different stages of malaria.

    Conclusion: In this study, a high-throughput affinity proteomics approach was used to find protein profiles in plasma linked to P. falciparum infection and malaria disease progression. The proteins presented herein are mainly involved in inflammatory response, cellular adhesion and as constituents of erythrocyte membrane. These findings have a great potential to provide increased conceptual understanding of host-parasite interaction and malaria pathogenesis.

  • 64.
    Rutebemberwa, Elizeus
    et al.
    Dept of Healht Policy, Planning and Management, Makerere University School of Public Health, Kampala, Uganda.
    Nsabagasani, Xavier
    Pariyo, George
    Tomson, Göran
    Peterson, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Kallander, Karin
    Use of drugs, perceived drug efficacy and preferred providers for febrile children: implications for home management of fever2009In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 8, no 1, p. 131-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Community distribution of anti-malarials and antibiotics has been recommended as a strategy to reduce the under-five mortality due to febrile illnesses in sub-Saharan Africa. However, drugs distributed in these interventions have been considered weak by some caretakers and utilization of community medicine distributors has been low. The aim of the study was to explore caretakers' use of drugs, perceptions of drug efficacy and preferred providers for febrile children in order to make suggestions for community management of pneumonia and malaria. METHODS: The study was conducted in eastern Uganda using four focus group discussions with fathers and mothers of children under five; and eight key informant interviews with health workers in government and non-governmental organization facilities, community medicine distributors, and attendants in drug shops and private clinics. Caretakers were asked the drugs they use for treatment of fever, why they considered them efficacious, and the providers they go to and why they go there. Health providers were interviewed on their opinions of caretakers' perceptions of drugs and providers. Analysis was done using content analysis. RESULTS: Drugs that have been phased out as first-line treatment for malaria, such as chloroquine and sulphadoxine/pyrimethamine, are still perceived as efficacious. Use of drugs depended on perception of the disease, cost and drug availability. There were divergent views about drug efficacy concerning drug combinations, side effects, packaging, or using drugs over time. Bitter taste and high cost signified high efficacy for anti-malarials. Government facilities were preferred for conducting diagnostic investigations and attending to serious illnesses, but often lacked drugs and did not treat people fast. Drug shops were preferred for having a variety of drugs, attending to clients promptly and offering treatment on credit. However, drug shops were considered disadvantageous since they lacked diagnostic capability and had unqualified providers. CONCLUSION: Community views about drug efficacy are divergent and some may divert caretakers from obtaining efficacious drugs for febrile illness. Interventions should address these perceptions, equip community medicine distributors with capacity to do diagnostic investigations and provide a constant supply of drugs. Subsidized efficacious drugs could be made available in the private sector.

  • 65.
    Rutebemberwa, Elizeus
    et al.
    Dept of Health Policy Planning and Management, Makerere University School of Public Health, Kampala, Uganda.
    Pariyo, George
    Peterson, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Tomson, Göran
    Kallander, Karin
    Utilization of public or private health care providers by febrile children after user fee removal in Uganda2009In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 8, p. 45-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Despite investments in providing free government health services in Uganda, many caretakers still seek treatment from the drug shops/private clinics. The study aimed to assess determinants for use of government facilities or drug shops/private clinics for febrile illnesses in children under five. METHODS: Structured questionnaires were administered to caretakers in 1078 randomly selected households in the Iganga - Mayuge Demographic Surveillance site. Those with children who had had fever in the previous two weeks and who had sought care from outside the home were interviewed on presenting symptoms and why they chose the provider they went to. Symptoms children presented with and reasons for seeking care from government facilities were compared with those of drug shops/private clinics. RESULTS: Of those who sought care outside the home, 62.7% (286/456) had first gone to drug shops/private clinics and 33.1% (151/456) first went to government facilities. Predictors of having gone to government facilities with a febrile child were child presenting with vomiting (OR 2.07; 95% CI 1.10 - 3.89) and perceiving that the health providers were qualified (OR 10.32; 95% CI 5.84 - 18.26) or experienced (OR 1.93; 95% CI 1.07 - 3.48). Those who took the febrile child to drug shops/private clinics did so because they were going there to get first aid (OR 0.20; 95% CI 0.08 - 0.52). CONCLUSION: Private providers offer 'first aid' to caretakers with febrile children. Government financial assistance to health care providers should not stop at government facilities. Multi-faceted interventions in the private sector and implementation of community case management of febrile children through community medicine distributors could increase the proportion of children who access quality care promptly.

  • 66. Saulo, Eleonor C.
    et al.
    Forsberg, Birger C.
    Premji, Zul
    Montgomery, Scott M.
    Örebro University, School of Health and Medical Sciences.
    Björkman, Anders
    Willingness and ability to pay for artemisinin-based combination therapy in rural Tanzania2008In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 7, p. 227-Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to analyse willingness to pay (WTP) and ability to pay (ATP) for ACT for children below five years of age in a rural setting in Tanzania before the introduction of artemisinin-based combination therapy (ACT) as first-line treatment for uncomplicated malaria. Socio-economic factors associated with WTP and expectations on anti-malaria drugs, including ACT, were also explored.

    Methods

    Structured interviews and focus group discussions were held with mothers, household heads, health-care workers and village leaders in Ishozi, Gera and Ishunju wards in north-west Tanzania in 2004. Contingent valuation method (CVM) was used with "take-it-or-leave-it" as the eliciting method, expressed as WTP for a full course of ACT for a child and households' opportunity cost of ACT was used to assess ATP. The study included descriptive analyses with multivariate adjustment for potential confounding factors.

    Results

    Among 265 mothers and household heads, 244 (92%, CI = 88%–95%) were willing to pay Tanzanian Shillings (TSh) 500 (US$ 0.46) for a child's dose of ACT, but only 55% (49%–61%) were willing to pay more than TSh 500. Mothers were more often willing to pay than male household heads (adjusted odds ratio = 2.1, CI = 1.2–3.6). Socio-economic status had no significant effect on WTP. The median annual non-subsidized ACT cost for clinical malaria episodes in an average household was calculated as US$ 6.0, which would represent 0.9% of the average total consumption expenditures as estimated from official data in 2001. The cost of non-subsidized ACT represented 7.0% of reported total annual expenditure on food and 33.0% of total annual expenditure on health care.

    "Rapid effect," "no adverse effect" and "inexpensive" were the most desired features of an anti-malarial drug.

    Conclusion

    WTP for ACT in this study was less than its real cost and a subsidy is, therefore, needed to enable its equitable affordability. The decision taken in Tanzania to subsidize Coartem® fully at governmental health care facilities and at a consumer price of TSh 300–500 (US$ 0.28–0.46) at special designated shops through the programme of Accredited Drug Dispensing Outlets (ADDOs) appears to be well founded.

  • 67. Shelton, Jennifer M. G.
    et al.
    Corran, Patrick
    Risley, Paul
    Silva, Nilupa
    Hubbart, Christina
    Jeffreys, Anna
    Rowlands, Kate
    Craik, Rachel
    Cornelius, Victoria
    Hensmann, Meike
    Molloy, Sile
    Sepulveda, Nuno
    Clark, Taane G.
    Band, Gavin
    Clarke, Geraldine M.
    Spencer, Christopher C. A.
    Kerasidou, Angeliki
    Campino, Susana
    Auburn, Sarah
    Tall, Adama
    Ly, Alioune Badara
    Mercereau-Puijalon, Odile
    Sakuntabhai, Anavaj
    Djimde, Abdoulaye
    Maiga, Boubacar
    Toure, Ousmane
    Doumbo, Ogobara K.
    Dolo, Amagana
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Mangano, Valentina D.
    Verra, Frederica
    Modiano, David
    Bougouma, Edith
    Sirima, Sodiomon B.
    Ibrahim, Muntaser
    Hussain, Ayman
    Eid, Nahid
    Elzein, Abier
    Mohammed, Hiba
    Elhassan, Ahmed
    Elhassan, Ibrahim
    Williams, Thomas N.
    Ndila, Carolyne
    Macharia, Alexander
    Marsh, Kevin
    Manjurano, Alphaxard
    Reyburn, Hugh
    Lemnge, Martha
    Ishengoma, Deus
    Carter, Richard
    Karunaweera, Nadira
    Fernando, Deepika
    Dewasurendra, Rajika
    Drakeley, Christopher J.
    Riley, Eleanor M.
    Kwiatkowski, Dominic P.
    Rockett, Kirk A.
    Genetic determinants of anti-malarial acquired immunity in a large multi-centre study2015In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 14, article id 333Article in journal (Refereed)
    Abstract [en]

    Background: Many studies report associations between human genetic factors and immunity to malaria but few have been reliably replicated. These studies are usually country-specific, use small sample sizes and are not directly comparable due to differences in methodologies. This study brings together samples and data collected from multiple sites across Africa and Asia to use standardized methods to look for consistent genetic effects on anti-malarial antibody levels. Methods: Sera, DNA samples and clinical data were collected from 13,299 individuals from ten sites in Senegal, Mali, Burkina Faso, Sudan, Kenya, Tanzania, and Sri Lanka using standardized methods. DNA was extracted and typed for 202 Single Nucleotide Polymorphisms with known associations to malaria or antibody production, and antibody levels to four clinical grade malarial antigens [AMA1, MSP1, MSP2, and (NANP) 4] plus total IgE were measured by ELISA techniques. Regression models were used to investigate the associations of clinical and genetic factors with antibody levels. Results: Malaria infection increased levels of antibodies to malaria antigens and, as expected, stable predictors of anti-malarial antibody levels included age, seasonality, location, and ethnicity. Correlations between antibodies to blood-stage antigens AMA1, MSP1 and MSP2 were higher between themselves than with antibodies to the (NANP)(4) epitope of the pre-erythrocytic circumsporozoite protein, while there was little or no correlation with total IgE levels. Individuals with sickle cell trait had significantly lower antibody levels to all blood-stage antigens, and recessive homozygotes for CD36 (rs321198) had significantly lower anti-malarial antibody levels to MSP2. Conclusion: Although the most significant finding with a consistent effect across sites was for sickle cell trait, its effect is likely to be via reducing a microscopically positive parasitaemia rather than directly on antibody levels. However, this study does demonstrate a framework for the feasibility of combining data from sites with heterogeneous malaria transmission levels across Africa and Asia with which to explore genetic effects on anti-malarial immunity.

  • 68.
    Sundell, Kerstin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Jagannathan, Prasanna
    Univ Calif San Francisco, San Francisco Gen Hosp, Dept Med, San Francisco, CA 94143 USA..
    Huang, Liusheng
    Univ Calif San Francisco, Dept Clin Pharm, San Francisco, CA USA..
    Bigira, Victor
    Infect Dis Res Collaborat, Kampala, Uganda..
    Kapisi, James
    Infect Dis Res Collaborat, Kampala, Uganda..
    Kakuru, Mary M.
    Infect Dis Res Collaborat, Kampala, Uganda..
    Savic, Rada
    Univ Calif San Francisco, Dept Bioengn & Therapeut, San Francisco, CA USA..
    Kamya, Moses R.
    Makerere Univ, Coll Hlth Sci, Dept Med, Kampala, Uganda..
    Dorsey, Grant
    Univ Calif San Francisco, San Francisco Gen Hosp, Dept Med, San Francisco, CA 94143 USA..
    Aweeka, Francesca
    Univ Calif San Francisco, Dept Clin Pharm, San Francisco, CA USA..
    Variable piperaquine exposure significantly impacts protective efficacy of monthly dihydroartemisinin-piperaquine for the prevention of malaria in Ugandan children2015In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 14, article id 368Article in journal (Refereed)
    Abstract [en]

    Background: Anti-malarial chemoprevention with dihydroartemisinin-piperaquine (DHA/PQ) is a promising tool for malaria control, but its efficacy in children may be limited by inadequate drug exposure. Methods: Children were enrolled in a non directly-observed trial of DHA/PQ chemoprevention in a high transmission setting in Uganda. Children were randomized at 6 months of age to no chemoprevention (n = 89) or monthly DHA/PQ (n = 87) and followed through 24 months of age, with pharmacokinetic sampling performed at variable times following monthly dosing of DHA/PQ. A previously published pharmacokinetic model was used to estimate piperaquine (PQ) exposure in each child, and associations between PQ exposure and the protective efficacy (PE) of DHA/PQ were explored. Results: The incidence of malaria was 6.83 and 3.09 episodes per person year at risk in the no chemoprevention and DHA/PQ arms, respectively (PE 54 %, 95 % CI 39-66 %, P < 0.001). Among children randomized to DHA/PQ, 493 pharmacokinetic samples were collected. Despite nearly 100 % reported adherence to study drug administration at home, there was wide variability in PQ exposure, and children were stratified into three groups based on average PQ exposure during the intervention that was determined by model generated percentiles (low, n = 40; medium, n = 37, and high, n = 10). Gender and socioeconomic factors were not significantly associated with PQ exposure. In multivariate models, the PE of DHA/PQ was 31 % in the low PQ exposure group (95 % CI 6-49 %, P = 0.02), 67 % in the medium PQ exposure group (95 % CI 54-76 %, P < 0.001), and 97 % in the high PQ exposure group (95 % CI 89-99 %, P < 0.001). Conclusions: The protective efficacy of DHA/PQ chemoprevention in young children was strongly associated with higher drug exposure; in children with the highest PQ exposure, monthly DHA/PQ chemoprevention was nearly 100 % protective against malaria. Strategies to ensure good adherence to monthly dosing and optimize drug exposure are critical to maximize the efficacy of this promising malaria control strategy.

  • 69.
    Surowiec, Izabella
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Gouveia-Figueira, Sandra
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Orikiiriza, Judy
    Lindquist, Elisabeth
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Bonde, Mari
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Magambo, Jimmy
    Muhinda, Charles
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Normark, Johan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Trygg, Johan
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    The oxylipin and endocannabidome responses in acute phase Plasmodium falciparum malaria in children2017In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 16, article id 358Article in journal (Refereed)
    Abstract [en]

    Background: Oxylipins and endocannabinoids are low molecular weight bioactive lipids that are crucial for initiation and resolution of inflammation during microbial infections. Metabolic complications in malaria are recognized contributors to severe and fatal malaria, but the impact of malaria infection on the production of small lipid derived signalling molecules is unknown. Knowledge of immunoregulatory patterns of these molecules in malaria is of great value for better understanding of the disease and improvement of treatment regimes, since the action of these classes of molecules is directly connected to the inflammatory response of the organism.

    Methods: Detection of oxylipins and endocannabinoids from plasma samples from forty children with uncomplicated and severe malaria as well as twenty controls was done after solid phase extraction followed by chromatography mass spectrometry analysis. The stable isotope dilution method was used for compound quantification. Data analysis was done with multivariate (principal component analysis (PCA), orthogonal partial least squares discriminant analysis (OPLS-DA (R)) and univariate approaches (receiver operating characteristic (ROC) curves, t tests, correlation analysis).

    Results: Forty different oxylipin and thirteen endocannabinoid metabolites were detected in the studied samples, with one oxylipin (thromboxane B2, TXB2) in significantly lower levels and four endocannabinoids (OEA, PEA, DEA and EPEA) at significantly higher levels in infected individuals as compared to controls according to t test analysis with Bonferroni correction. Three oxylipins (13-HODE, 9-HODE and 13-oxo-ODE) were higher in severe compared to uncomplicated malaria cases according to the results from multivariate analysis. Observed changes in oxylipin levels can be connected to activation of cytochrome P450 (CYP) and 5-lipoxygenase (5-LOX) metabolic pathways in malaria infected individuals compared to controls, and related to increased levels of all linoleic acid oxylipins in severe patients compared to uncomplicated ones. The endocannabinoids were extremely responsive to malaria infection with majority of this class of molecules found at higher levels in infected individuals compared to controls.

    Conclusions: It was possible to detect oxylipin and endocannabinoid molecules that can be potential biomarkers for differentiation between malaria infected individuals and controls and between different classes of malaria. Metabolic pathways that could be targeted towards an adjunctive therapy in the treatment of malaria were also pinpointed.

  • 70.
    Sylvester, Boniphace
    et al.
    Muhimbili Univ Hlth & Allied Sci, Sch Publ Hlth & Social Sci, Dept Parasitol & Med Entomol, POB 65001, Dar Es Salaam, Tanzania..
    Gasarasi, Dinah B.
    Muhimbili Univ Hlth & Allied Sci, Sch Publ Hlth & Social Sci, Dept Parasitol & Med Entomol, POB 65001, Dar Es Salaam, Tanzania..
    Aboud, Said
    Muhimbili Univ Hlth & Allied Sci, Sch Med, Dept Microbiol & Immunol, POB 65001, Dar Es Salaam, Tanzania..
    Tarimo, Donath
    Muhimbili Univ Hlth & Allied Sci, Sch Publ Hlth & Social Sci, Dept Parasitol & Med Entomol, POB 65001, Dar Es Salaam, Tanzania..
    Massawe, Siriel
    Muhimbili Univ Hlth & Allied Sci, Sch Med, Dept Obstet & Gynaecol, POB 65001, Dar Es Salaam, Tanzania..
    Mpembeni, Rose
    Muhimbili Univ Hlth & Allied Sci, Sch Publ Hlth & Social Sci, Dept Community Med, POB 65001, Dar Es Salaam, Tanzania..
    Swedberg, Göte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Prenatal exposure to Plasmodium falciparum increases frequency and shortens time from birth to first clinical malaria episodes during the first two years of life: prospective birth cohort study2016In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 15, article id 379Article in journal (Refereed)
    Abstract [en]

    Background: Prenatal exposure to Plasmodium falciparum affects development of protective immunity and susceptibility to subsequent natural challenges with similar parasite antigens. However, the nature of these effects has not been fully elucidated. The aim of this study was to determine the effect of prenatal exposure to P. falciparum on susceptibility to natural malaria infection, with a focus on median time from birth to first clinical malaria episode and frequency of clinical malaria episodes in the first 2 years of life.

    Methods: A prospective birth cohort study was conducted in Rufiji district in Tanzania, between January 2013 and December 2015. Infants born to mothers with P. falciparum in the placenta at time of delivery were defined as exposed, and infants born to mothers without P. falciparum parasites in placenta were defined as unexposed. Placental infection was established by histological techniques. Out of 206 infants recruited, 41 were in utero exposed to P. falciparum and 165 infants were unexposed. All infants were monitored for onset of clinical malaria episodes in the first 2 years of life. The outcome measure was time from birth to first clinical malaria episode, defined by fever (>= 37 degrees C) and microscopically determined parasitaemia. Median time to first clinical malaria episode between exposed and unexposed infants was assessed using Kaplan-Meier survival analysis and comparison was done by log rank. Association of clinical malaria episodes with prenatal exposure to P. falciparum was assessed by multivariate binary logistic regression. Comparative analysis of mean number of clinical malaria episodes between exposed and unexposed infants was done using independent sample t test.

    Results: The effect of prenatal exposure to P. falciparum infection on clinical malaria episodes was statistically significant (Odds Ratio of 4.79, 95 % CI 2.21-10.38, p < 0.01) when compared to other confounding factors. Median time from birth to first clinical malaria episode for exposed and unexposed infants was 32 weeks (95 % CI 30.88-33.12) and 37 weeks (95 % CI 35.25-38.75), respectively, and the difference was statistically significant (p = 0.003). The mean number of clinical malaria episodes in exposed and unexposed infants was 0.51 and 0.30 episodes/infant, respectively, and the difference was statistically significant (p = 0.038).

    Conclusions: Prenatal exposure to P. falciparum shortens time from birth to first clinical malaria episode and increases frequency of clinical malaria episodes in the first 2 years of life.

  • 71. Tangteerawatana, Piyatida
    et al.
    Perlmann, Hedvig
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Hayano, Masashi
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Kalambaheti, Thareerat
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Khusmith, Srisin
    IL4 gene polymorphism and previous malaria experiences manipulate anti-Plasmodium falciparum antibody isotype profiles in complicated and uncomplicated malaria.2009In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 8, no 1, p. 286-Article in journal (Refereed)
    Abstract [en]

    ABSTRACT: BACKGROUND: The IL4-590 gene polymorphism has been shown to be associated with elevated levels of anti-Plasmodium falciparum IgG antibodies and parasite intensity in the malaria protected Fulani of West Africa. This study aimed to investigate the possible impact of IL4-590C/T polymorphism on anti-P. falciparum IgG subclasses and IgE antibodies levels and the alteration of malaria severity in complicated and uncomplicated malaria patients with or without previous malaria experiences. METHODS: Anti-P.falciparum IgG subclasses and IgE antibodies in plasma of complicated and uncomplicated malaria patients with or without previous malaria experiences were analysed using ELISA. IL4-590 polymorphisms were genotyped using RFLP-PCR. Statistical analyses of the IgG subclasses and IgE levels were done by Oneway ANOVA. Genotype differences were tested by Chi-squared test. RESULTS: The IL4-590T allele was significantly associated with anti-P. falciparum IgG3 antibody levels in patients with complicated (P=0.031), but not with uncomplicated malaria (P=0.622). Complicated malaria patients with previous malaria experiences carrying IL4-590TT genotype had significantly lower levels of anti-P. falciparum IgG3 (P=0.0156), while uncomplicated malaria patients with previous malaria experiences carrying the same genotype had significantly higher levels (P=0.0206) compared to their IL4-590 counterparts. The different anti-P. falciparum IgG1 and IgG3 levels among IL4-590 genotypes were observed. Complicated malaria patients with previous malaria experiences tended to have lower IgG3 levels in individuals carrying TT when compared to CT genotypes (P=0.075). In contrast, complicated malaria patients without previous malaria experiences carrying CC genotype had significantly higher anti-P. falciparum IgG1 than those carrying either CT or TT genotypes (P=0.004, P=0.002, respectively). CONCLUSIONS: The results suggest that IL4-590C or T alleles participated differently in the regulation of anti-malarial antibody isotype profiles in primary and secondary malaria infection and, therefore, could play an important role in alteration of malaria severity.

  • 72. Topalis, Pantelis
    et al.
    Mitraka, Elvira
    Bujila, Ioana
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Deligianni, Elena
    Dialynas, Emmanuel
    Siden-Kiamos, Inga
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Louis, Christos
    IDOMAL: an ontology for malaria2010In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 9, p. 230-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Ontologies are rapidly becoming a necessity for the design of efficient information technology tools, especially databases, because they permit the organization of stored data using logical rules and defined terms that are understood by both humans and machines. This has as consequence both an enhanced usage and interoperability of databases and related resources. It is hoped that IDOMAL, the ontology of malaria will prove a valuable instrument when implemented in both malaria research and control measures. METHODS: The OBOEdit2 software was used for the construction of the ontology. IDOMAL is based on the Basic Formal Ontology (BFO) and follows the rules set by the OBO Foundry consortium. RESULTS: The first version of the malaria ontology covers both clinical and epidemiological aspects of the disease, as well as disease and vector biology. IDOMAL is meant to later become the nucleation site for a much larger ontology of vector borne diseases, which will itself be an extension of a large ontology of infectious diseases (IDO). The latter is currently being developed in the frame of a large international collaborative effort. CONCLUSIONS: IDOMAL, already freely available in its first version, will form part of a suite of ontologies that will be used to drive IT tools and databases specifically constructed to help control malaria and, later, other vector-borne diseases. This suite already consists of the ontology described here as well as the one on insecticide resistance that has been available for some time. Additional components are being developed and introduced into IDOMAL.

  • 73.
    Zacarias, Orlando P.
    et al.
    Stockholm University, Faculty of Social Sciences, Department of Computer and Systems Sciences. Eduardo Mondlane University, Moçambique.
    Andersson, Mikael
    Stockholm University, Faculty of Science, Department of Mathematics.
    Mapping malaria incidence distribution that accounts for environmental factors in Maputo Province - Mozambique2010In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 9, article id 79Article in journal (Refereed)
    Abstract [en]

    Background: The objective was to study if an association exists between the incidence of malaria and some weather parameters in tropical Maputo province, Mozambique. Methods: A Bayesian hierarchical model to malaria count data aggregated at district level over a two years period is formulated. This model made it possible to account for spatial area variations. The model was extended to include environmental covariates temperature and rainfall. Study period was then divided into two climate conditions: rainy and dry seasons. The incidences of malaria between the two seasons were compared. Parameter estimation and inference were carried out using MCMC simulation techniques based on Poisson variation. Model comparisons are made using DIC. Results: For winter season, in 2001 the temperature covariate with estimated value of -8.88 shows no association to malaria incidence. In year 2002, the parameter estimation of the same covariate resulted in 5.498 of positive level of association. In both years rainfall covariate determines no dependency to malaria incidence. Malaria transmission is higher in wet season with both covariates positively related to malaria with posterior means 1.99 and 2.83 in year 2001. For 2002 only temperature is associated to malaria incidence with estimated value 2.23. Conclusions: The incidence of malaria in year 2001, presents an independent spatial pattern for temperature in summer and for rainfall in winter seasons respectively. In year 2002 temperature determines the spatial pattern of malaria incidence in the region. Temperature influences the model in cases where both covariates are introduced in winter and summer season. Its influence is extended to the summer model with temperature covariate only. It is reasonable to state that with the occurrence of high temperatures, malaria incidence had certainly escalated in this year.

  • 74.
    Zacarias, Orlando P.
    et al.
    Stockholm University, Faculty of Social Sciences, Department of Computer and Systems Sciences. Eduardo Mondlane University, Mozambique.
    Andersson, Mikael
    Stockholm University, Faculty of Science, Department of Mathematics.
    Spatial and temporal patterns of malaria incidence in Mozambique2011In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 10, article id 189Article in journal (Refereed)
    Abstract [en]

    Background: The objective of this study is to analyze the spatial and temporal patterns of malaria incidence as to determine the means by which climatic factors such as temperature, rainfall and humidity affect its distribution in Maputo province, Mozambique. Methods: This study presents a model of malaria that evolves in space and time in Maputo province-Mozambique, over a ten years period (1999-2008). The model incorporates malaria cases and their relation to environmental variables. Due to incompleteness of climatic data, a multiple imputation technique is employed. Additionally, the whole province is interpolated through a Gaussian process. This method overcomes the misalignment problem of environmental variables (available at meteorological stations points) and malaria cases (available as aggregates for every district - area). Markov Chain Monte Carlo (MCMC) methods are used to obtain posterior inference and Deviance Information Criteria (DIC) to perform model comparison. Results: A Bayesian model with interaction terms was found to be the best fitted model. Malaria incidence was associated to humidity and maximum temperature. Malaria risk increased with maximum temperature over 28 degrees C (relative risk (RR) of 0.0060 and 95% Bayesian credible interval (CI) of 0.00033-0.0095) and humidity (relative risk (RR) of 0.00741 and 95% Bayesian CI 0.005141-0.0093). The results would suggest that additional non-climatic factors including socio-economic status, elevation, etc. also influence malaria transmission in Mozambique. Conclusions: These results demonstrate the potential of climate predictors particularly, humidity and maximum temperature in explaining malaria incidence risk for the studied period in Maputo province. Smoothed maps obtained as monthly average of malaria incidence allowed to visualize months of initial and peak transmission. They also illustrate a variation on malaria incidence risk that might not be related to climatic factors. However, these factors are still determinant for malaria transmission and intensity in the region.

  • 75.
    Zacarias, Orlando P.
    et al.
    Stockholm University, Faculty of Social Sciences, Department of Computer and Systems Sciences. Eduardo Mondlane University, Mozambique .
    Majlender, Peter
    Stockholm University, Faculty of Social Sciences, Department of Computer and Systems Sciences.
    Comparison of infant malaria incidence in districts of Maputo province, Mozambique2011In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 10, article id 93Article in journal (Refereed)
    Abstract [en]

    Background: Malaria is one of the principal health problems in Mozambique, representing 48% of total external consultations and 63% of paediatric hospital admissions in rural and general hospitals with 26.7% of total mortality. Plasmodium falciparum is responsible for 90% of all infections being also the species associated with most severe cases. The aim of this study was to identify zones of high malaria risk, showing their spatially and temporal pattern. Methods: Space and time Poison model for the analysis of malaria data is proposed. This model allows for the inclusion of environmental factors: rainfall, temperature and humidity as predictor variables. Modelling and inference use the fully Bayesian approach via Markov Chain Monte Carlo (MCMC) simulation techniques. The methodology is applied to analyse paediatric data arising from districts of Maputo province, Mozambique, between 2007 and 2008. Results: Malaria incidence risk is greater for children in districts of Manhica, Matola and Magude. Rainfall and humidity are significant predictors of malaria incidence. The risk increased with rainfall (relative risk - RR: .006761, 95% interval: .001874, .01304), and humidity (RR: .049, 95% interval: .03048, .06531). Malaria incidence was found to be independent of temperature. Conclusions: The model revealed a spatial and temporal pattern of malaria incidence. These patterns were found to exhibit a stable malaria transmission in most non-coastal districts. The findings may be useful for malaria control, planning and management.

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