Prasanna Jagannathan

All Publications

• Vδ2+ T cell response to malaria correlates with protection from infection but is attenuated with repeated exposure. Scientific reports Jagannathan, P., Lutwama, F., Boyle, M. J., Nankya, F., Farrington, L. A., McIntyre, T. I., Bowen, K., Naluwu, K., Nalubega, M., Musinguzi, K., Sikyomu, E., Budker, R., Katureebe, A., Rek, J., Greenhouse, B., Dorsey, G., Kamya, M. R., Feeney, M. E. 2017; 7 (1): 11487

  Abstract

  Vδ2(+) γδ T cells are semi-innate T cells that expand markedly following P. falciparum (Pf) infection in naïve adults, but are lost and become dysfunctional among children repeatedly exposed to malaria. The role of these cells in mediating clinical immunity (i.e. protection against symptoms) to malaria remains unclear. We measured Vδ2(+) T cell absolute counts at acute and convalescent malaria timepoints (n = 43), and Vδ2(+) counts, cellular phenotype, and cytokine production following in vitro stimulation at asymptomatic visits (n = 377), among children aged 6 months to 10 years living in Uganda. Increasing age was associated with diminished in vivo expansion following malaria, and lower Vδ2 absolute counts overall, among children living in a high transmission setting. Microscopic parasitemia and expression of the immunoregulatory markers Tim-3 and CD57 were associated with diminished Vδ2(+) T cell pro-inflammatory cytokine production. Higher Vδ2 pro-inflammatory cytokine production was associated with protection from subsequent Pf infection, but also with an increased odds of symptoms once infected. Vδ2(+) T cells may play a role in preventing malaria infection in children living in endemic settings; progressive loss and dysfunction of these cells may represent a disease tolerance mechanism that contributes to the development of clinical immunity to malaria.

  View details for DOI 10.1038/s41598-017-10624-3

  View details for PubMedID 28904345

• Effective Antimalarial Chemoprevention in Childhood Enhances the Quality of CD4(+) T Cells and Limits Their Production of Immunoregulatory Interleukin 10 JOURNAL OF INFECTIOUS DISEASES Jagannathan, P., Bowen, K., Nankya, F., McIntyre, T. I., Auma, A., Wamala, S., Sikyomu, E., Naluwu, K., Nalubega, M., Boyle, M. J., Farrington, L. A., Bigira, V., Kapisi, J., Aweeka, F., Greenhouse, B., Kamya, M., Dorsey, G., Feeney, M. E. 2016; 214 (2): 329-338

  Abstract

  Experimental inoculation of viable Plasmodium falciparum sporozoites administered with chemoprevention targeting blood-stage parasites results in protective immunity. It is unclear whether chemoprevention similarly enhances immunity following natural exposure to malaria.We assessed P. falciparum-specific T-cell responses among Ugandan children who were randomly assigned to receive monthly dihydroartemisinin-piperaquine (DP; n = 87) or no chemoprevention (n = 90) from 6 to 24 months of age, with pharmacologic assessments for adherence, and then clinically followed for an additional year.During the intervention, monthly DP reduced malaria episodes by 55% overall (P < .001) and by 97% among children who were highly adherent to DP (P < .001). In the year after the cessation of chemoprevention, children who were highly adherent to DP had a 55% reduction in malaria incidence as compared to children given no chemoprevention (P = .004). Children randomly assigned to receive DP had higher frequencies of blood-stage specific CD4(+) T cells coproducing interleukin-2 and tumor necrosis factor α (P = .003), which were associated with protection from subsequent clinical malaria and parasitemia, and fewer blood-stage specific CD4(+) T cells coproducing interleukin-10 and interferon γ (P = .001), which were associated with increased risk of malaria.In this setting, effective antimalarial chemoprevention fostered the development of CD4(+) T cells that coproduced interleukin 2 and tumor necrosis factor α and were associated with prospective protection, while limiting CD4(+) T-cell production of the immunoregulatory cytokine IL-10.

  View details for DOI 10.1093/infdis/jiw147

  View details for Web of Science ID 000379822900021

  View details for PubMedID 27067196

• Dihydroartemisinin-Piperaquine for the Prevention of Malaria in Pregnancy NEW ENGLAND JOURNAL OF MEDICINE Kakuru, A., Jagannathan, P., Muhindo, M. K., Natureeba, P., Awori, P., Nakalembe, M., Opira, B., Olwoch, P., Ategeka, J., Nayebare, P., Clark, T. D., Feeney, M. E., Charlebois, E. D., Rizzuto, G., Muehlenbachs, A., Havlir, D. V., Kamya, M. R., Dorsey, G. 2016; 374 (10): 928-939

  Abstract

  Intermittent treatment with sulfadoxine-pyrimethamine is widely recommended for the prevention of malaria in pregnant women in Africa. However, with the spread of resistance to sulfadoxine-pyrimethamine, new interventions are needed.We conducted a double-blind, randomized, controlled trial involving 300 human immunodeficiency virus (HIV)-uninfected pregnant adolescents or women in Uganda, where sulfadoxine-pyrimethamine resistance is widespread. We randomly assigned participants to a sulfadoxine-pyrimethamine regimen (106 participants), a three-dose dihydroartemisinin-piperaquine regimen (94 participants), or a monthly dihydroartemisinin-piperaquine regimen (100 participants). The primary outcome was the prevalence of histopathologically confirmed placental malaria.The prevalence of histopathologically confirmed placental malaria was significantly higher in the sulfadoxine-pyrimethamine group (50.0%) than in the three-dose dihydroartemisinin-piperaquine group (34.1%, P=0.03) or the monthly dihydroartemisinin-piperaquine group (27.1%, P=0.001). The prevalence of a composite adverse birth outcome was lower in the monthly dihydroartemisinin-piperaquine group (9.2%) than in the sulfadoxine-pyrimethamine group (18.6%, P=0.05) or the three-dose dihydroartemisinin-piperaquine group (21.3%, P=0.02). During pregnancy, the incidence of symptomatic malaria was significantly higher in the sulfadoxine-pyrimethamine group (41 episodes over 43.0 person-years at risk) than in the three-dose dihydroartemisinin-piperaquine group (12 episodes over 38.2 person-years at risk, P=0.001) or the monthly dihydroartemisinin-piperaquine group (0 episodes over 42.3 person-years at risk, P<0.001), as was the prevalence of parasitemia (40.5% in the sulfadoxine-pyrimethamine group vs. 16.6% in the three-dose dihydroartemisinin-piperaquine group [P<0.001] and 5.2% in the monthly dihydroartemisinin-piperaquine group [P<0.001]). In each treatment group, the risk of vomiting after administration of any dose of the study agents was less than 0.4%, and there were no significant differences among the groups in the risk of adverse events.The burden of malaria in pregnancy was significantly lower among adolescent girls or women who received intermittent preventive treatment with dihydroartemisinin-piperaquine than among those who received sulfadoxine-pyrimethamine, and monthly treatment with dihydroartemisinin-piperaquine was superior to three-dose dihydroartemisinin-piperaquine with regard to several outcomes. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development; ClinicalTrials.gov number, NCT02163447.).

  View details for DOI 10.1056/NEJMoa1509150

  View details for Web of Science ID 000371660000006

  View details for PubMedID 26962728

• Loss and dysfunction of Vd2? ?d T cells are associated with clinical tolerance to malaria. Science translational medicine Jagannathan, P., Kim, C. C., Greenhouse, B., Nankya, F., Bowen, K., Eccles-James, I., Muhindo, M. K., Arinaitwe, E., Tappero, J. W., Kamya, M. R., Dorsey, G., Feeney, M. E. 2014; 6 (251): 251ra117-?

  Abstract

  Although clinical immunity to malaria eventually develops among children living in endemic settings, the underlying immunologic mechanisms are not known. The Vδ2(+) subset of γδ T cells have intrinsic reactivity to malaria antigens, can mediate killing of Plasmodium falciparum merozoites, and expand markedly in vivo after malaria infection in previously naïve hosts, but their role in mediating immunity in children repeatedly exposed to malaria is unclear. We evaluated γδ T cell responses to malaria among 4-year-old children enrolled in a longitudinal study in Uganda. We found that repeated malaria was associated with reduced percentages of Vδ2(+) γδ T cells in peripheral blood, decreased proliferation and cytokine production in response to malaria antigens, and increased expression of immunoregulatory genes. Further, loss and dysfunction of proinflammatory Vδ2(+) γδ T cells were associated with a reduced likelihood of symptoms upon subsequent P. falciparum infection. Together, these results suggest that repeated malaria infection during childhood results in progressive loss and dysfunction of Vδ2(+) γδ T cells that may facilitate immunological tolerance of the parasite.

  View details for DOI 10.1126/scitranslmed.3009793

  View details for PubMedID 25163477

• IFN gamma/IL-10 Co-producing Cells Dominate the CD4 Response to Malaria in Highly Exposed Children PLOS PATHOGENS Jagannathan, P., Eccles-James, I., Bowen, K., Nankya, F., Auma, A., Wamala, S., Ebusu, C., Muhindo, M. K., Arinaitwe, E., Briggs, J., Greenhouse, B., Tappero, J. W., Kamya, M. R., Dorsey, G., Feeney, M. E. 2014; 10 (1)

  Abstract

  Although evidence suggests that T cells are critical for immunity to malaria, reliable T cell correlates of exposure to and protection from malaria among children living in endemic areas are lacking. We used multiparameter flow cytometry to perform a detailed functional characterization of malaria-specific T cells in 78 four-year-old children enrolled in a longitudinal cohort study in Tororo, Uganda, a highly malaria-endemic region. More than 1800 episodes of malaria were observed in this cohort, with no cases of severe malaria. We quantified production of IFNγ, TNFα, and IL-10 (alone or in combination) by malaria-specific T cells, and analyzed the relationship of this response to past and future malaria incidence. CD4(+) T cell responses were measurable in nearly all children, with the majority of children having CD4(+) T cells producing both IFNγ and IL-10 in response to malaria-infected red blood cells. Frequencies of IFNγ/IL10 co-producing CD4(+) T cells, which express the Th1 transcription factor T-bet, were significantly higher in children with ≥2 prior episodes/year compared to children with <2 episodes/year (P<0.001) and inversely correlated with duration since malaria (Rho = -0.39, P<0.001). Notably, frequencies of IFNγ/IL10 co-producing cells were not associated with protection from future malaria after controlling for prior malaria incidence. In contrast, children with <2 prior episodes/year were significantly more likely to exhibit antigen-specific production of TNFα without IL-10 (P = 0.003). While TNFα-producing CD4(+) T cells were not independently associated with future protection, the absence of cells producing this inflammatory cytokine was associated with the phenotype of asymptomatic infection. Together these data indicate that the functional phenotype of the malaria-specific T cell response is heavily influenced by malaria exposure intensity, with IFNγ/IL10 co-producing CD4(+) T cells dominating this response among highly exposed children. These CD4(+) T cells may play important modulatory roles in the development of antimalarial immunity.

  View details for DOI 10.1371/journal.ppat.1003864

  View details for Web of Science ID 000332640900031

  View details for PubMedID 24415936

• Response to "Antiretroviral Therapy With Efavirenz in HIV-Infected Pregnant Women: Understanding the Possible Mechanisms for Drug-Drug Interaction". Clinical pharmacology and therapeutics Jagannathan, P., Kajubi, R., Aweeka, F. T. 2018

  View details for DOI 10.1002/cpt.963

  View details for PubMedID 29322501

• Intermittent Preventive Treatment with Dihydroartemisinin-piperaquine for the Prevention of Malaria among HIV-infected Pregnant Women. journal of infectious diseases Natureeba, P., Kakuru, A., Muhindo, M., Littmann, E., Ochieng, T., Ategeka, J., Koss, C. A., Plenty, A., Charlebois, E. D., Clark, T. D., Nzarubara, B., Nakalembe, M., Cohan, D., Rizzuto, G., Muehlenbachs, A., Ruel, T., Jagannathan, P., Havlir, D. V., Kamya, M. R., Dorsey, G. 2017

  Abstract

  Daily trimethoprim-sulfamethoxazole (TMP-SMX) and insecticide treated nets (ITNs) remain the main interventions for prevention of malaria in HIV-infected pregnant women in Africa. However, antifolate and pyrethroid resistance threaten the effectiveness of these intervention and new ones are needed.We conducted a double-blind randomized placebo-controlled trial comparing daily TMP-SMX plus monthly dihydroartemisinin-piperaquine (DP) to daily TMP-SMX alone in HIV-infected pregnant women in an area of Uganda where indoor residual spraying of insecticide (IRS) had recently been implemented. Participants were enrolled between 12-28 weeks gestation and provided an ITN. The primary outcome was placental malaria by histopathology (active or past infection). Secondary outcomes included incidence of malaria; parasite prevalence; and adverse birth outcomes.All 200 women enrolled were followed through delivery and the primary outcome was assessed in 194. There was no statistically significant difference in the risk of placental malaria by histopathology between the daily TMP-SMX plus DP and daily TMP-SMX alone arms (6.1 vs. 3.1%, RR=1.96, 95%CI 0.50-7.61, P=0.50). Similarly, there were no differences in secondary outcomes.Among HIV-infected pregnant women in the setting of IRS, adding monthly DP to daily TMP-SMX did not reduce the risk of placental or maternal malaria or improve birth outcomes.

  View details for DOI 10.1093/infdis/jix110

  View details for PubMedID 28329368

• Antiretroviral Therapy With Efavirenz Accentuates Pregnancy-Associated Reduction of Dihydroartemisinin-Piperaquine Exposure During Malaria Chemoprevention. Clinical pharmacology & therapeutics Kajubi, R., Huang, L., Jagannathan, P., Chamankhah, N., WERE, M., Ruel, T., Koss, C. A., Kakuru, A., Mwebaza, N., Kamya, M., Havlir, D., Dorsey, G., Rosenthal, P. J., Aweeka, F. T. 2017

  Abstract

  Dihydroartemisinin (DHA)-piperaquine is promising for malaria chemoprevention in pregnancy. We assessed impacts of pregnancy and efavirenz-based antiretroviral therapy on exposure to DHA and piperaquine in pregnant Ugandan women. Intensive sampling was performed at 28 weeks gestation in 31 HIV-uninfected pregnant women, in 27 HIV-infected pregnant women receiving efavirenz, and in 30 HIV-uninfected non-pregnant women. DHA peak concentration and area under the concentration time curve (AUC0-8hr ) were 50% and 47% lower, respectively, and piperaquine AUC0-21d was 40% lower in pregnant women compared to non-pregnant women. DHA AUC0-8hr and piperaquine AUC0-21d were 27% and 38% lower, respectively in pregnant women receiving efavirenz compared to HIV-uninfected pregnant women. Exposure to DHA and piperaquine were lower among pregnant women and particularly in women on efavirenz, suggesting a need for dose modifications. The study of modified dosing strategies for these populations is urgently needed. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/cpt.664

  View details for PubMedID 28187497

• CD4 T Regulatory Cells in Infants Exposed to Malaria In Utero. Open forum infectious diseases Prahl, M., Jagannathan, P., McIntyre, T. I., Auma, A., Wamala, S., Nalubega, M., Musinguzi, K., Naluwu, K., Sikyoma, E., Budker, R., Odorizzi, P., Kakuru, A., Havlir, D. V., Kamya, M. R., Dorsey, G., Feeney, M. E. 2017; 4 (1): ofx022-?

  Abstract

  Sex differences in the immune response and in infectious disease susceptibility have been well described, although the mechanisms underlying these differences remain incompletely understood. We evaluated the frequency of cord blood CD4 T cell subsets in a highly malaria-exposed birth cohort of mother-infant pairs in Uganda by sex. We found that frequencies of cord blood regulatory T cell ([Treg] CD4(+)CD25(+)FoxP3(+)CD127(lo/-)) differed by infant sex, with significantly lower frequencies of Tregs in female than in male neonates (P = .006). When stratified by in utero malaria exposure status, this difference was observed in the exposed, but not in the unexposed infants.

  View details for DOI 10.1093/ofid/ofx022

  View details for PubMedID 28480292

  View details for PubMedCentralID PMC5414097

• Both inflammatory and regulatory cytokine responses to malaria are blunted with increasing age in highly exposed children. Malaria journal Farrington, L., Vance, H., Rek, J., Prahl, M., Jagannathan, P., Katureebe, A., Arinaitwe, E., Kamya, M. R., Dorsey, G., Feeney, M. E. 2017; 16 (1): 499

  Abstract

  Young children are at greatest risk for malaria-associated morbidity and mortality. The immune response of young children differs in fundamental ways from that of adults, and these differences likely contribute to the increased susceptibility of children to severe malaria and to their delayed development of immunity. Elevated levels of pro-inflammatory cytokines and chemokines in the peripheral blood during acute infection contribute to the control of parasitaemia, but are also responsible for much of the immunopathology seen during symptomatic disease. Clinical immunity to malaria may depend upon the ability to regulate these pro-inflammatory responses, possibly through mechanisms of immunologic tolerance. In order to explore the effect of age on the immune response to malaria and the development of clinical immunity, cytokines and chemokines were measured in the plasma of children at day 0 of an acute malaria episode and during convalescence.Younger children presenting with acute malaria exhibited much higher levels of TNF, IL2, and IL6, as well as increased Th1 associated chemokines IP10, MIG, and MCP1, compared to older children with acute malaria. Additionally, the regulatory cytokines IL10 and TNFRI were dramatically elevated in younger children compared to older children during acute infection, indicating that regulatory as well as pro-inflammatory cytokine responses are dampened in later childhood.Together these data suggest that there is a profound blunting of the cytokine and chemokine response to malaria among older children residing in endemic settings, which may be due to repeated malaria exposure, intrinsic age-based differences in the immune response, or both.

  View details for DOI 10.1186/s12936-017-2148-6

  View details for PubMedID 29284469

• The Development of Plasmodium falciparum-Specific IL10 CD4 T Cells and Protection from Malaria in Children in an Area of High Malaria Transmission. Frontiers in immunology Boyle, M. J., Jagannathan, P., Bowen, K., McIntyre, T. I., Vance, H. M., Farrington, L. A., Schwartz, A., Nankya, F., Naluwu, K., Wamala, S., Sikyomu, E., Rek, J., Greenhouse, B., Arinaitwe, E., Dorsey, G., Kamya, M. R., Feeney, M. E. 2017; 8: 1329

  Abstract

  Cytokine-producing CD4 T cells have important roles in immunity against Plasmodium falciparum (Pf) malaria. However, the factors influencing functional differentiation of Pf-specific CD4 T cells in naturally exposed children are not well understood. Moreover, it is not known which CD4 T-cell cytokine-producing subsets are most critical for protection. We measured Pf-specific IFNγ-, IL10-, and TNFα-producing CD4 T-cell responses by multi-parametric flow cytometry in 265 children aged 6 months to 10 years enrolled in a longitudinal observational cohort in a high malaria transmission site in Uganda. We found that both age and parasite burden were independently associated with cytokine production by CD4 T cells. IL10 production by IFNγ+ CD4 T cells was higher in younger children and in those with high-parasite burden during recent infection. To investigate the role of CD4 T cells in immunity to malaria, we measured associations of Pf-specific CD4 cytokine-producing cells with the prospective risk of Pf infection and clinical malaria, adjusting for household exposure to Pf-infected mosquitos. Overall, the prospective risk of infection was not associated with the total frequency of Pf-specific CD4 T cells, nor of any cytokine-producing CD4 subset. However, the frequency of CD4 cells producing IL10 but not inflammatory cytokines (IFNγ and TNFα) was associated with a decreased risk of clinical malaria once infected. These data suggest that functional polarization of the CD4 T-cell response may modulate the clinical manifestations of malaria and play a role in naturally acquired immunity.

  View details for DOI 10.3389/fimmu.2017.01329

  View details for PubMedID 29097996

  View details for PubMedCentralID PMC5653696

• Impact of intermittent preventive treatment during pregnancy on Plasmodium falciparum drug resistance-mediating polymorphisms in Uganda. The Journal of infectious diseases Conrad, M. D., Mota, D., Foster, M., Tukwasibwe, S., Legac, J., Tumwebaze, P., Whalen, M., Kakuru, A., Nayebare, P., Wallender, E., Havlir, D. V., Jagannathan, P., Huang, L., Aweeka, F., Kamya, M. R., Dorsey, G., Rosenthal, P. J. 2017

  Abstract

  In a recent trial of intermittent preventive treatment in pregnancy (IPTp) in Uganda, dihydroartemisinin-piperaquine (DP) was superior to sulfadoxine-pyrimethamine (SP) in preventing maternal and placental malaria.We compared genotypes using sequencing, fluorescent microsphere, and qPCR assays at loci associated with drug resistance in Plasmodium falciparum isolated from subjects receiving DP or SP.Considering aminoquinoline resistance, DP was associated with increased prevalences of mutations at pfmdr1 N86Y, pfmdr1 Y184F, and pfcrt K76T compared to SP (64.6% vs 27.4%, p<0.001; 93.9% vs 59.2%, p<0.001; and 87.7% vs 75.4%, p=0.03, respectively). Increasing plasma piperaquine concentration at the time of parasitemia was associated with increasing pfmdr1 86Y prevalence; no infections with the N86 genotype occurred with piperaquine >2.75 ng/ml. pfkelch13 propeller domain polymorphisms previously associated with artemisinin resistance were not identified. Recently identified markers of piperaquine resistance were uncommon and not associated with DP. Considering antifolate resistance, SP was associated with increased prevalence of a 5 mutation haplotype (pfdhfr 51I, 59R, and 108N; pfdhps 437G and 581G) compared to DP (90.8% vs 60.0%, p=0.001).IPTp selected for genotypes associated with decreased sensitivity to treatment regimens, but genotypes associated with clinically relevant DP resistance in Asia have not emerged in Uganda.

  View details for DOI 10.1093/infdis/jix421

  View details for PubMedID 28968782

• Protective effect of indoor residual spraying of insecticide on preterm birth among pregnant women with HIV in Uganda: A secondary data analysis. The Journal of infectious diseases Roh, M. E., Shiboski, S., Natureeba, P., Kakuru, A., Muhindo, M., Ochieng, T., Plenty, A., Koss, C. A., Clark, T. D., Awori, P., Nakalambe, M., Cohan, D., Jagannathan, P., Gosling, R., Havlir, D. V., Kamya, M. R., Dorsey, G. 2017

  Abstract

  Recent evidence demonstrated improved birth outcomes among HIV-uninfected pregnant women protected by indoor residual spraying of insecticide (IRS). Evidence regarding its impact on HIV-infected pregnant women is lacking.Data were pooled from two studies conducted before-and-after an IRS campaign in Tororo, Uganda among HIV-infected pregnant women who received bednets, daily trimethoprim-sulfamethoxazole (TMP-SMX), and combination antiretroviral therapy (c-ART) at enrollment. Exposure was the proportion of pregnancy protected by IRS. Adverse birth outcomes included preterm birth, low birthweight, and fetal/neonatal death. Multivariate Poisson regression with robust standard errors was used to estimate risk ratios (RR).Of 565 women in our analysis, 380 (67%), 88 (16%), and 97 (17%) women were protected by IRS for 0%, >0-90%, and >90% of their pregnancy, respectively. Any IRS protection significantly reduced malaria incidence during pregnancy and placental malaria risk. Compared to no IRS protection, >90% IRS protection reduced preterm birth risk (RR=0.35; 95% CI: 0.15-0.84), with non-significant decreases in the risk of low birthweight (RR=0.68; 95% CI: 0.29-1.57) and fetal/neonatal death (RR=0.24; 95% CI: 0.04-1.52).Our exploratory analyses support the hypothesis that IRS may significantly reduce malaria and preterm birth risk among pregnant women with HIV receiving bednets, daily TMP-SMX, and c-ART.

  View details for DOI 10.1093/infdis/jix533

  View details for PubMedID 29029337

• Predicting optimal dihydroartemisinin-piperaquine regimens to prevent malaria during pregnancy for HIV-infected women receiving efavirenz. The Journal of infectious diseases Wallender, E., Vucicevic, K., Jagannathan, P., Huang, L., Natureeba, P., Kakura, A., Muhindo, M., Nakalembe, M., Havlir, D., Kamya, M., Aweeka, F., Dorsey, G., Rosenthal, P. J., Savic, R. M. 2017

  Abstract

  A monthly treatment course of dihydroartemisinin-piperaquine (DHA-PQ) effectively prevents malaria during pregnancy. However, a drug-drug interaction pharmacokinetic (PK) study found that pregnant HIV-infected women receiving efavirenz-based antiretroviral therapy (ART) had markedly reduced piperaquine exposure. This suggests the need for alternative DHA-PQ chemoprevention regimens in this population.Eighty-three HIV-infected pregnant women who received monthly DHA-PQ and efavirenz contributed longitudinal pharmacokinetic and QTc (25 women) data. Population PK and PK-QTc models for piperaquine were developed to consider the benefits (protective piperaquine coverage) and risks (QTc prolongation) of alternative DHA-PQ chemoprevention regimens. Protective piperaquine coverage was defined as maintaining a concentration >10 ng/ml for >95% of the chemoprevention period.Piperaquine clearance was 4,540 L/day. With monthly DHA-PQ (2,880 mg piperaquine), <1% of women achieved defined protective piperaquine coverage. Weekly (960 mg piperaquine) or low dose daily (320 or 160 mg piperaquine) regimens, achieved protective piperaquine coverage for 34% and >96% of women respectively. All regimens were safe, with ≤2% of women predicted to have ≥ 30 msec QTc increase.For HIV-infected pregnant women receiving efavirenz, low daily DHA-PQ dosing was predicted to improve protection against parasitemia and reduce risk of toxicity compared to monthly dosing.

  View details for DOI 10.1093/infdis/jix660

  View details for PubMedID 29272443

• Relationships between infection with Plasmodium falciparum during pregnancy, measures of placental malaria, and adverse birth outcomes. Malaria journal Kapisi, J., Kakuru, A., Jagannathan, P., Muhindo, M. K., Natureeba, P., Awori, P., Nakalembe, M., Ssekitoleko, R., Olwoch, P., Ategeka, J., Nayebare, P., Clark, T. D., Rizzuto, G., Muehlenbachs, A., Havlir, D. V., Kamya, M. R., Dorsey, G., Gaw, S. L. 2017; 16 (1): 400

  Abstract

  Malaria in pregnancy has been associated with maternal morbidity, placental malaria, and adverse birth outcomes. However, data are limited on the relationships between longitudinal measures of malaria during pregnancy, measures of placental malaria, and birth outcomes.This is a nested observational study of data from a randomized controlled trial of intermittent preventive therapy during pregnancy among 282 participants with assessment of placental malaria and delivery outcomes. HIV-uninfected pregnant women were enrolled at 12-20 weeks of gestation. Symptomatic malaria during pregnancy was measured using passive surveillance and monthly detection of asymptomatic parasitaemia using loop-mediated isothermal amplification (LAMP). Placental malaria was defined as either the presence of parasites in placental blood by microscopy, detection of parasites in placental blood by LAMP, or histopathologic evidence of parasites or pigment. Adverse birth outcomes assessed included low birth weight (LBW), preterm birth (PTB), and small for gestational age (SGA) infants.The 282 women were divided into three groups representing increasing malaria burden during pregnancy. Fifty-two (18.4%) had no episodes of symptomatic malaria or asymptomatic parasitaemia during the pregnancy, 157 (55.7%) had low malaria burden (0-1 episodes of symptomatic malaria and < 50% of samples LAMP+), and 73 (25.9%) had high malaria burden during pregnancy (≥ 2 episodes of symptomatic malaria or ≥ 50% of samples LAMP+). Women with high malaria burden had increased risks of placental malaria by blood microscopy and LAMP [aRR 14.2 (1.80-111.6) and 4.06 (1.73-9.51), respectively], compared to the other two groups combined. Compared with women with no malaria exposure during pregnancy, the risk of placental malaria by histopathology was higher among low and high burden groups [aRR = 3.27 (1.32-8.12) and aRR = 7.07 (2.84-17.6), respectively]. Detection of placental parasites by any method was significantly associated with PTB [aRR 5.64 (1.46-21.8)], and with a trend towards increased risk for LBW and SGA irrespective of the level of malaria burden during pregnancy.Higher malaria burden during pregnancy was associated with placental malaria and together with the detection of parasites in the placenta were associated with increased risk for adverse birth outcomes. Trial Registration Current Controlled Trials Identifier NCT02163447.

  View details for DOI 10.1186/s12936-017-2040-4

  View details for PubMedID 28982374

  View details for PubMedCentralID PMC5629777

• Timing of in utero malaria exposure influences fetal CD4 T cell regulatory versus effector differentiation MALARIA JOURNAL Prahl, M., Jagannathan, P., McIntyre, T. I., Auma, A., Farrington, L., Wamala, S., Nalubega, M., Musinguzi, K., Naluwu, K., Sikyoma, E., Budker, R., Vance, H., Odorizzi, P., Nayebare, P., Ategeka, J., Kakuru, A., Havlir, D. V., Kamya, M. R., Dorsey, G., Feeney, M. E. 2016; 15

  Abstract

  In malaria-endemic areas, the first exposure to malaria antigens often occurs in utero when the fetal immune system is poised towards the development of tolerance. Children exposed to placental malaria have an increased risk of clinical malaria in the first few years of life compared to unexposed children. Recent work has suggested the potential of pregnancy-associated malaria to induce immune tolerance in children living in malaria-endemic areas. A study was completed to evaluate the effect of malaria exposure during pregnancy on fetal immune tolerance and effector responses.Using cord blood samples from a cohort of mother-infant pairs followed from early in pregnancy until delivery, flow cytometry analysis was completed to assess the relationship between pregnancy-associated malaria and fetal cord blood CD4 and dendritic cell phenotypes.Cord blood FoxP3(+) Treg counts were higher in infants born to mothers with Plasmodium parasitaemia early in pregnancy (12-20 weeks of gestation; p = 0.048), but there was no association between Treg counts and the presence of parasites in the placenta at the time of delivery (by loop-mediated isothermal amplification (LAMP); p = 0.810). In contrast, higher frequencies of activated CD4 T cells (CD25(+)FoxP3(-)CD127(+)) were observed in the cord blood of neonates with active placental Plasmodium infection at the time of delivery (p = 0.035). This population exhibited evidence of effector memory differentiation, suggesting priming of effector T cells in utero. Lastly, myeloid dendritic cells were higher in the cord blood of infants with histopathologic evidence of placental malaria (p < 0.0001).Together, these data indicate that in utero exposure to malaria drives expansion of both regulatory and effector T cells in the fetus, and that the timing of this exposure has a pivotal role in determining the polarization of the fetal immune response.

  View details for DOI 10.1186/s12936-016-1545-6

  View details for Web of Science ID 000384846400001

  View details for PubMedID 27717402

• Quantifying Heterogeneous Malaria Exposure and Clinical Protection in a Cohort of Ugandan Children. journal of infectious diseases Rodriguez-Barraquer, I., Arinaitwe, E., Jagannathan, P., Boyle, M. J., Tappero, J., Muhindo, M., Kamya, M. R., Dorsey, G., Drakeley, C., Ssewanyana, I., Smith, D. L., Greenhouse, B. 2016; 214 (7): 1072-1080

  Abstract

  Plasmodium falciparum malaria remains a leading cause of childhood morbidity and mortality. There are important gaps in our understanding of the factors driving the development of antimalaria immunity as a function of age and exposure.We used data from a cohort of 93 children participating in a clinical trial in Tororo, Uganda, an area of very high exposure to P. falciparum We jointly quantified individual heterogeneity in the risk of infection and the development of immunity against infection and clinical disease.Results showed significant heterogeneity in the hazard of infection and independent effects of age and cumulative number of infections on the risk of infection and disease. The risk of developing clinical malaria upon infection decreased on average by 6% (95% confidence interval [CI], 0%-12%) for each additional year of age and by 2% (95% CI, 1%-3%) for each additional prior infection. Children randomly assigned to receive dihydroartemisinin-piperaquine for treatment appeared to develop immunity more slowly than those receiving artemether-lumefantrine.Heterogeneity in P. falciparum exposure and immunity can be independently evaluated using detailed longitudinal studies. Improved understanding of the factors driving immunity will provide key information to anticipate the impact of malaria-control interventions and to understand the mechanisms of clinical immunity.

  View details for DOI 10.1093/infdis/jiw301

  View details for PubMedID 27481862

• Characterizing microscopic and submicroscopic malaria parasitaemia at three sites with varied transmission intensity in Uganda MALARIA JOURNAL Rek, J., Katrak, S., Obasi, H., Nayebare, P., Katureebe, A., Kakande, E., Arinaitwe, E., Nankabirwa, J. I., Jagannathan, P., Drakeley, C., Staedke, S. G., Smith, D. L., Bousema, T., Kamya, M., Rosenthal, P. J., Dorsey, G., Greenhouse, B. 2016; 15

  Abstract

  Parasite prevalence is a key metric used to quantify the burden of malaria and assess the impact of control strategies. Most published estimates of parasite prevalence are based on microscopy and likely underestimate true prevalence.Thick smear microscopy was performed in cohorts of children (aged 6 month to 10 years) and adults every 90 days over 2 years, at three sites of varying transmission intensity in Uganda. Microscopy-negative samples were tested for sub-microscopic parasitaemia using loop-mediated isothermal amplification (LAMP). Generalized estimating equation models were used to evaluate associations between age and parasitaemia, factors associated with sub-microscopic infection and associations between parasitaemia and haemoglobin.A total of 9260 samples were collected from 1245 participants. Parasite prevalence among children across the three sites was 7.4, 9.4 and 28.8 % by microscopy and 21.3, 31.8 and 69.0 % by microscopy plus LAMP. Parasite prevalence among adults across the three sites was 3.1, 3.0 and 5.2 % by microscopy and 18.8, 24.2 and 53.5 % by microscopy plus LAMP. Among those with parasitaemia, adults and persons recently treated with anti-malarial therapy had the highest prevalence of sub-microscopic infection. Children with sub-microscopic or microscopic parasitaemia had lower mean haemoglobin levels compared to children with no detectable parasites.Across a range of transmission intensities in Uganda, microscopy vastly underestimated parasite prevalence, especially among adults.

  View details for DOI 10.1186/s12936-016-1519-8

  View details for Web of Science ID 000383665400001

  View details for PubMedID 27628178

• Reductions in malaria in pregnancy and adverse birth outcomes following indoor residual spraying of insecticide in Uganda MALARIA JOURNAL Muhindo, M. K., Kakuru, A., Natureeba, P., Awori, P., Olwoch, P., Ategeka, J., Nayebare, P., Clark, T. D., Muehlenbachs, A., Roh, M., Mpeka, B., Greenhouse, B., Havlir, D. V., Kamya, M. R., Dorsey, G., Jagannathan, P. 2016; 15

  Abstract

  Indoor residual spraying of insecticide (IRS) is a key intervention for reducing the burden of malaria in Africa. However, data on the impact of IRS on malaria in pregnancy and birth outcomes is limited.An observational study was conducted within a trial of intermittent preventive therapy during pregnancy in Tororo, Uganda. Women were enrolled at 12-20 weeks of gestation between June and October 2014, provided with insecticide-treated bed nets, and followed through delivery. From December 2014 to February 2015, carbamate-containing IRS was implemented in Tororo district for the first time. Exact spray dates were collected for each household. The exposure of interest was the proportion of time during a woman's pregnancy under protection of IRS, with three categories of protection defined: no IRS protection, >0-20 % IRS protection, and 20-43 % IRS protection. Outcomes assessed included malaria incidence and parasite prevalence during pregnancy, placental malaria, low birth weight (LBW), pre-term delivery, and fetal/neonatal deaths.Of 289 women followed, 134 had no IRS protection during pregnancy, 90 had >0-20 % IRS protection, and 65 had >20-43 % protection. During pregnancy, malaria incidence (0.49 vs 0.10 episodes ppy, P = 0.02) and parasite prevalence (20.0 vs 8.9 %, P < 0.001) were both significantly lower after IRS. At the time of delivery, the prevalence of placental parasitaemia was significantly higher in women with no IRS protection (16.8 %) compared to women with 0-20 % (1.1 %, P = 0.001) or >20-43 % IRS protection (1.6 %, P = 0.006). Compared to women with no IRS protection, those with >20-43 % IRS protection had a lower risk of LBW (20.9 vs 3.1 %, P = 0.002), pre-term birth (17.2 vs 1.5 %, P = 0.006), and fetal/neonatal deaths (7.5 vs 0 %, P = 0.03).In this setting, IRS was temporally associated with lower malaria parasite prevalence during pregnancy and at delivery, and improved birth outcomes. IRS may represent an important tool for combating malaria in pregnancy and for improving birth outcomes in malaria-endemic settings. Trial Registration Current Controlled Trials Identifier NCT02163447.

  View details for DOI 10.1186/s12936-016-1489-x

  View details for Web of Science ID 000382535500004

  View details for PubMedID 27566109

• Frequent Malaria Drives Progressive V delta 2 T-Cell Loss, Dysfunction, and CD16 Up-regulation During Early Childhood JOURNAL OF INFECTIOUS DISEASES Farrington, L. A., Jagannathan, P., McIntyre, T. I., Vance, H. M., Bowen, K., Boyle, M. J., Nankya, F., Wamala, S., Auma, A., Nalubega, M., Sikyomu, E., Naluwu, K., Bigira, V., Kapisi, J., Dorsey, G., Kamya, M. R., Feeney, M. E. 2016; 213 (9): 1483-1490

  Abstract

  γδ T cells expressing Vδ2 may be instrumental in the control of malaria, because they inhibit the replication of blood-stage parasites in vitro and expand during acute malaria infection. However, Vδ2 T-cell frequencies and function are lower among children with heavy prior malaria exposure. It remains unclear whether malaria itself is driving this loss. Here we measure Vδ2 T-cell frequency, cytokine production, and degranulation longitudinally in Ugandan children enrolled in a malaria chemoprevention trial from 6 to 36 months of age. We observed a progressive attenuation of the Vδ2 response only among children incurring high rates of malaria. Unresponsive Vδ2 T cells were marked by expression of CD16, which was elevated in the setting of high malaria transmission. Moreover, chemoprevention during early childhood prevented the development of dysfunctional Vδ2 T cells. These observations provide insight into the role of Vδ2 T cells in the immune response to chronic malaria.

  View details for DOI 10.1093/infdis/jiv600

  View details for Web of Science ID 000376295800018

  View details for PubMedID 26667315

  View details for PubMedCentralID PMC4813738

• B cell sub-types following acute malaria and associations with clinical immunity (vol 15, 139, 2016) MALARIA JOURNAL Sullivan, R. T., Ssewanyana, I., Wamala, S., Nankya, F., Jagannathan, P., Tappero, J. W., Mayanja-Kizza, H., Muhindo, M. K., Arinaitwe, E., Kamya, M., Dorsey, G., Feeney, M. E., Riley, E. M., Drakeley, C. J., Greenhouse, B. 2016; 15

  View details for DOI 10.1186/s12936-016-1236-3

  View details for Web of Science ID 000373485200005

• Variable piperaquine exposure significantly impacts protective efficacy of monthly dihydroartemisinin-piperaquine for the prevention of malaria in Ugandan children MALARIA JOURNAL Sundell, K., Jagannathan, P., Huang, L., Bigira, V., Kapisi, J., Kakuru, M. M., Savic, R., Kamya, M. R., Dorsey, G., Aweeka, F. 2015; 14

  Abstract

  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.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.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).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.Current Controlled Trials Identifier NCT00948896.

  View details for DOI 10.1186/s12936-015-0908-8

  View details for Web of Science ID 000361786600002

  View details for PubMedID 26403465

• Effector Phenotype of Plasmodium falciparum-Specific CD4(+) T Cells Is Influenced by Both Age and Transmission Intensity in Naturally Exposed Populations JOURNAL OF INFECTIOUS DISEASES Boyle, M. J., Jagannathan, P., Bowen, K., McIntyre, T. I., Vance, H. M., Farrington, L. A., Greenhouse, B., Nankya, F., Rek, J., Katureebe, A., Arinaitwe, E., Dorsey, G., Kamya, M. R., Feeney, M. E. 2015; 212 (3): 416-425

  Abstract

  Mechanisms mediating immunity to malaria remain unclear, but animal data and experimental human vaccination models suggest a critical role for CD4(+) T cells. Advances in multiparametric flow cytometry have revealed that the functional quality of pathogen-specific CD4(+) T cells determines immune protection in many infectious models. Little is known about the functional characteristics of Plasmodium-specific CD4(+) T-cell responses in immune and nonimmune individuals.We compared T-cell responses to Plasmodium falciparum among household-matched children and adults residing in settings of high or low malaria transmission in Uganda. Peripheral blood mononuclear cells were stimulated with P. falciparum antigen, and interferon γ (IFN-γ), interleukin 2, interleukin 10, and tumor necrosis factor α (TNF-α) production was analyzed via multiparametric flow cytometry.We found that the magnitude of the CD4(+) T-cell responses was greater in areas of high transmission but similar between children and adults in each setting type. In the high-transmission setting, most P. falciparum-specific CD4(+) T-cells in children produced interleukin 10, while responses in adults were dominated by IFN-γ and TNF-α. In contrast, in the low-transmission setting, responses in both children and adults were dominated by IFN-γ and TNF-α.These findings highlight major differences in the CD4(+) T-cell response of immune adults and nonimmune children that may be relevant for immune protection from malaria.

  View details for DOI 10.1093/infdis/jiv054

  View details for Web of Science ID 000357824300011

  View details for PubMedID 25646355

• Decline of FoxP3+Regulatory CD4 T Cells in Peripheral Blood of Children Heavily Exposed to Malaria PLOS PATHOGENS Boyle, M. J., Jagannathan, P., Farrington, L. A., Eccles-James, I., Wamala, S., McIntyre, T. I., Vance, H. M., Bowen, K., Nankya, F., Auma, A., Nalubega, M., Sikyomu, E., Naluwu, K., Rek, J., Katureebe, A., Bigira, V., Kapisi, J., Tappero, J., Muhindo, M. K., Greenhouse, B., Arinaitwe, E., Dorsey, G., Kamya, M. R., Feeney, M. E. 2015; 11 (7)

  Abstract

  FoxP3+ regulatory CD4 T cells (Tregs) help to maintain the delicate balance between pathogen-specific immunity and immune-mediated pathology. Prior studies suggest that Tregs are induced by P. falciparum both in vivo and in vitro; however, the factors influencing Treg homeostasis during acute and chronic infections, and their role in malaria immunopathogenesis, remain unclear. We assessed the frequency and phenotype of Tregs in well-characterized cohorts of children residing in a region of high malaria endemicity in Uganda. We found that both the frequency and absolute numbers of FoxP3+ Tregs in peripheral blood declined markedly with increasing prior malaria incidence. Longitudinal measurements confirmed that this decline occurred only among highly malaria-exposed children. The decline of Tregs from peripheral blood was accompanied by reduced in vitro induction of Tregs by parasite antigen and decreased expression of TNFR2 on Tregs among children who had intense prior exposure to malaria. While Treg frequencies were not associated with protection from malaria, there was a trend toward reduced risk of symptomatic malaria once infected with P. falciparum among children with lower Treg frequencies. These data demonstrate that chronic malaria exposure results in altered Treg homeostasis, which may impact the development of antimalarial immunity in naturally exposed populations.

  View details for DOI 10.1371/journal.ppat.1005041

  View details for Web of Science ID 000359365200048

  View details for PubMedID 26182204

• IFN gamma Responses to Pre-erythrocytic and Blood-stage Malaria Antigens Exhibit Differential Associations With Past Exposure and Subsequent Protection JOURNAL OF INFECTIOUS DISEASES Jagannathan, P., Nankya, F., Stoyanov, C., Eccles-James, I., Sikyomu, E., Naluwu, K., Wamala, S., Nalubega, M., Briggs, J., Bowen, K., Bigira, V., Kapisi, J., Kamya, M. R., Dorsey, G., Feeney, M. E. 2015; 211 (12): 1987-1996

  Abstract

  The malaria-specific T-cell response is believed to be important for protective immunity. Antimalarial chemoprevention may affect this response by altering exposure to malaria antigens.We performed interferon γ (IFNγ) ELISpot assays to assess the cellular immune response to blood-stage and pre-erythrocytic antigens longitudinally from 1 to 3 years of age in 196 children enrolled in a randomized trial of antimalarial chemoprevention in Tororo, Uganda, an area of high transmission intensity.IFNγ responses to blood-stage antigens, particularly MSP1, were frequently detected, strongly associated with recent malaria exposure, and lower in those adherent to chemoprevention compared to nonadherent children and those randomized to no chemoprevention. IFNγ responses to pre-erythrocytic antigens were infrequent and similar between children randomized to chemoprevention or no chemoprevention. Responses to blood-stage antigens were not associated with subsequent protection from malaria (aHR 0.96, P = .83), but responses to pre-erythrocytic antigens were associated with protection after adjusting for prior malaria exposure (aHR 0.52, P = .009).In this high transmission setting, IFNγ responses to blood-stage antigens were common and associated with recent exposure to malaria but not protection from subsequent malaria. Responses to pre-erythrocytic antigens were uncommon, not associated with exposure but were associated with protection from subsequent malaria.

  View details for DOI 10.1093/infdis/jiu814

  View details for Web of Science ID 000355675600017

  View details for PubMedID 25520427

• FCRL5 Delineates Functionally Impaired Memory B Cells Associated with Plasmodium falciparum Exposure PLOS PATHOGENS Sullivan, R. T., Kim, C. C., Fontana, M. F., Feeney, M. E., Jagannathan, P., Boyle, M. J., Drakeley, C. J., Ssewanyana, I., Nankya, F., Mayanja-Kizza, H., Dorsey, G., Greenhouse, B. 2015; 11 (5)

  Abstract

  Exposure to Plasmodium falciparum is associated with circulating "atypical" memory B cells (atMBCs), which appear similar to dysfunctional B cells found in HIV-infected individuals. Functional analysis of atMBCs has been limited, with one report suggesting these cells are not dysfunctional but produce protective antibodies. To better understand the function of malaria-associated atMBCs, we performed global transcriptome analysis of these cells, obtained from individuals living in an area of high malaria endemicity in Uganda. Comparison of gene expression data suggested down-modulation of B cell receptor signaling and apoptosis in atMBCs compared to classical MBCs. Additionally, in contrast to previous reports, we found upregulation of Fc receptor-like 5 (FCRL5), but not FCRL4, on atMBCs. Atypical MBCs were poor spontaneous producers of antibody ex vivo, and higher surface expression of FCRL5 defined a distinct subset of atMBCs compromised in its ability to produce antibody upon stimulation. Moreover, higher levels of P. falciparum exposure were associated with increased frequencies of FCRL5+ atMBCs. Together, our findings suggest that FCLR5+ identifies a functionally distinct, and perhaps dysfunctional, subset of MBCs in individuals exposed to P. falciparum.

  View details for DOI 10.1371/journal.ppat.1004894

  View details for Web of Science ID 000355269300038

  View details for PubMedID 25993340

• Efficacy and safety of three regimens for the prevention of malaria in young HIV-exposed Ugandan children: a randomized controlled trial AIDS Kamya, M. R., Kapisi, J., Bigira, V., Clark, T. D., Kinara, S., Mwangwa, F., Muhindo, M. K., Kakuru, A., Aweeka, F. T., Huang, L., Jagannathan, P., Achan, J., Havlir, D. V., Rosenthal, P. J., Dorsey, G. 2014; 28 (18): 2701-2709

  Abstract

  Trimethoprim-sulfamethoxazole prophylaxis is recommended for HIV-exposed infants until breastfeeding ends and HIV infection has been excluded. Extending prophylaxis with a focus on preventing malaria may be beneficial in high transmission areas. We investigated three regimens for the prevention of malaria in young HIV-exposed children.An open-label, randomized controlled trial.Tororo, Uganda, a rural area with intense, year-round, malaria transmission.Two hundred infants aged 4-5 months enrolled and 186 randomized after cessation of breastfeeding and confirmed to be HIV uninfected (median 10 months of age).No chemoprevention, monthly sulfadoxine-pyrimethamine, daily trimethoprim-sulfamethoxazole or monthly dihydroartemisinin-piperaquine given from randomization to 24 months of age.The primary outcome was the incidence of malaria during the intervention period. Secondary outcomes included the incidence of hospitalization, diarrhoeal illness, or respiratory tract infection; prevalence of anaemia and asymptomatic parasitemia; measures of safety; and incidence of malaria over 1 year after the intervention was stopped.During the intervention, the incidence of malaria in the no chemoprevention group was 6.28 episodes per person-year at risk. Protective efficacy was 69% [95% confidence interval (95% CI) 53-80, P < 0.001] for dihydroartemisinin-piperaquine, 49% (95% CI 23-66, P = 0.001) for trimethoprim-sulfamethoxazole and 9% for sulfadoxine-pyrimethamine (95% CI -35 to 38, P = 0.65). There were no significant differences in any secondary outcomes, with the exception of a lower prevalence of asymptomatic parasitemia in the dihydroartemisinin-piperaquine arm.Monthly chemoprevention with dihydroartemisinin-piperaquine was well tolerated and associated with a significant reduction in malaria in young HIV-exposed children.

  View details for DOI 10.1097/QAD.0000000000000497

  View details for Web of Science ID 000345277300008

  View details for PubMedID 25493596

• Early parasite clearance following artemisinin-based combination therapy among Ugandan children with uncomplicated Plasmodium falciparum malaria MALARIA JOURNAL Muhindo, M. K., Kakuru, A., Jagannathan, P., Talisuna, A., Osilo, E., Orukan, F., Arinaitwe, E., Tappero, J. W., Kaharuza, F., Kamya, M. R., Dorsey, G. 2014; 13

  Abstract

  Artemisinin-based combination therapy (ACT) is widely recommended as first-line therapy for uncomplicated Plasmodium falciparum malaria worldwide. Artemisinin resistance has now been reported in Southeast Asia with a clinical phenotype manifested by slow parasite clearance. Although there are no reliable reports of artemisinin resistance in Africa, there is a need to better understand the dynamics of parasite clearance in African children treated with ACT in order to better detect the emergence of artemisinin resistance.Data from a cohort of Ugandan children four to five years old, enrolled in a longitudinal, randomized, clinical trial comparing two leading ACT, artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DP), were analysed. For all episodes of uncomplicated P. falciparum malaria over a 14-month period, daily blood smears were performed for three days following the initiation of therapy. Associations between pre-treatment variables of interest and persistent parasitaemia were estimated using multivariate, generalized, estimating equations with adjustment for repeated measures in the same patient.A total of 202 children were included, resulting in 416 episodes of malaria treated with AL and 354 episodes treated with DP. The prevalence of parasitaemia on days 1, 2, and 3 following initiation of therapy was 67.6, 5.6 and 0% in those treated with AL, and 52.2, 5.7 and 0.3% in those treated with DP. Independent risk factors for persistent parasitaemia on day 1 included treatment with AL vs DP (RR = 1.34, 95% CI 1.20-1.50, p < 0.001), having a temperature ≥38.0°C vs < 37.0°C (RR = 1.19, 95% CI 1.05-1.35, p = 0.007) and having a parasite density >20,000/μL vs <4,000/μL (RR = 3.37, 95% CI 2.44-4.49, p < 0.001). Independent risk factors for having persistent parasitaemia on day 2 included elevated temperature, higher parasite density, and being HIV infected.Among Ugandan children, parasite clearance following treatment with AL or DP was excellent with only one of 752 patients tested having a positive blood slide three days after initiation of therapy. The type of ACT given, pre-treatment temperature, pre-treatment parasite density and HIV status were associated with differences in persistent parasitaemia, one or two days following therapy.Current Controlled Trials Identifier NCT00527800.

  View details for DOI 10.1186/1475-2875-13-32

  View details for Web of Science ID 000331402500001

  View details for PubMedID 24468007

• The Effects of ACT Treatment and TS Prophylaxis on Plasmodium falciparum Gametocytemia in a Cohort of Young Ugandan Children AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE Kakuru, A., Jagannathan, P., Arinaitwe, E., Wanzira, H., Muhindo, M., Bigira, V., Osilo, E., Homsy, J., Kamya, M. R., Tappero, J. W., Dorsey, G. 2013; 88 (4): 736-743

  Abstract

  Artemisinin-based combination therapies (ACTs) and trimethoprim-sulfamethoxazole (TS) prophylaxis are important tools for malaria control, but there are concerns about their effect on gametocytes, the stage of the parasite responsible for transmission. We conducted a longitudinal clinical trial in a cohort of HIV-infected and uninfected children living in an area of high malaria transmission intensity in Uganda. Study participants were randomized to artemether-lumefantrine (AL) or dihydroartemisinin-piperaquine (DP) for all treatments of uncomplicated malaria (N = 4,380) as well as TS prophylaxis for different durations. The risks of gametocytemia detected by microscopy in the 28 days after antimalarial therapy were compared using multivariate analyses. The risk of gametocyte detection was significantly higher in patients treated with DP compared with AL (adjusted relative risk = 1.85, P < 0.001) and among children prescribed TS prophylaxis (adjusted relative risk = 1.76, P < 0.001). The risk of gametocytemia and its potential for increasing transmission should be considered when evaluating different ACTs and TS prophylaxis for malaria control.

  View details for DOI 10.4269/ajtmh.12-0654

  View details for Web of Science ID 000317024700023

  View details for PubMedID 23382157

• Increasing incidence of malaria in children despite insecticide-treated bed nets and prompt anti-malarial therapy in Tororo, Uganda MALARIA JOURNAL Jagannathan, P., Muhindo, M. K., Kakuru, A., Arinaitwe, E., Greenhouse, B., Tappero, J., Rosenthal, P. J., Kaharuza, F., Kamya, M. R., Dorsey, G. 2012; 11

  Abstract

  The burden of malaria has decreased in parts of Africa following the scaling up of control interventions. However, similar data are limited from high transmission settings.A cohort of 100 children, aged six weeks to 10 months of age, were enrolled in an area of high malaria transmission intensity and followed through 48 months of age. Children were given a long-lasting insecticide-treated bed net (LLIN) at enrolment and received all care, including monthly blood smears and treatment with artemisinin-based combination therapy (ACT) for uncomplicated malaria, at a dedicated clinic. The incidence of malaria was estimated by passive surveillance and associations between malaria incidence and age, calendar time and season were measured using generalized estimating equations.Reported compliance with LLINs was 98% based on monthly routine evaluations. A total of 1,633 episodes of malaria were observed, with a median incidence of 5.3 per person-year (PPY). There were only six cases of complicated malaria, all single convulsions. Malaria incidence peaked at 6.5 PPY at 23 months of age before declining to 3.5 PPY at 48 months. After adjusting for age and season, the risk of malaria increased by 52% from 2008 to 2011 (RR 1.52, 95% CI 1.10-2.09). Asymptomatic parasitaemia was uncommon (monthly prevalence <10%) and rarely observed prior to 24 months of age.In Tororo, despite provision of LLINs and prompt treatment with ACT, the incidence of malaria is very high and appears to be rising. Additional malaria control interventions in high transmission settings are likely needed.Current Controlled Trials Identifier NCT00527800.

  View details for DOI 10.1186/1475-2875-11-435

  View details for Web of Science ID 000313871300002

  View details for PubMedID 23273022

• Pantoea agglomerans pneumonia in a heart-lung transplant recipient: case report and a review of an emerging pathogen in immunocompromised hosts TRANSPLANT INFECTIOUS DISEASE Shubov, A., Jagannathan, P., Chin-Hong, P. V. 2011; 13 (5): 536-539

  Abstract

  Pantoea agglomerans is a gram-negative rod that is frequently found on the exterior of many plants, fruits, vegetables, and in soil, and it is used as a biopesticide in the agriculture industry. Recent reports have implicated P. agglomerans in systemic infections of immunocompromised hosts and neonates, as well as more localized infections in healthy hosts. P. agglomerans as a cause of hospital-acquired pneumonia has not been well characterized. We report a case of P. agglomerans pneumonia in a heart-lung transplant recipient following transplantation. The organism was susceptible to multiple antimicrobial agents and treated successfully with ertapenem. We review the patient's course and the relevant literature, and discuss implications for the future.

  View details for DOI 10.1111/j.1399-3062.2011.00630.x

  View details for Web of Science ID 000295837900017

  View details for PubMedID 21504526

• Life-threatening immune reconstitution inflammatory syndrome after Pneumocystis pneumonia: a cautionary case series AIDS Jagannathan, P., Davis, E., Jacobson, M., Huang, L. 2009; 23 (13): 1794-1796

  View details for DOI 10.1097/QAD.0b013e32832d9b20

  View details for Web of Science ID 000269333900024

  View details for PubMedID 19684486

• Comparisons of CD8(+) T Cells Specific for Human Immunodeficiency Virus, Hepatitis C Virus, and Cytomegalovirus Reveal Differences in Frequency, Immunodominance, Phenotype, and Interleukin-2 Responsiveness JOURNAL OF VIROLOGY Jagannathan, P., Osborne, C. M., Royce, C., Manion, M. M., Tilton, J. C., Li, L., Fischer, S., Hallahan, C. W., Metcalf, J. A., McLaughlin, M., Pipeling, M., McDyer, J. F., Manley, T. J., Meier, J. L., Altman, J. D., Hertel, L., Davey, R. T., Connors, M., Migueles, S. A. 2009; 83 (6): 2728-2742

  Abstract

  To better understand the components of an effective immune response to human immunodeficiency virus (HIV), the CD8(+) T-cell responses to HIV, hepatitis C virus (HCV), and cytomegalovirus (CMV) were compared with regard to frequency, immunodominance, phenotype, and interleukin-2 (IL-2) responsiveness. Responses were examined in rare patients exhibiting durable immune-mediated control over HIV, termed long-term nonprogressors (LTNP) or elite controllers, and patients with progressive HIV infection (progressors). The magnitude of the virus-specific CD8(+) T-cell response targeting HIV, CMV, and HCV was not significantly different between LTNP and progressors, even though their capacity to proliferate to HIV antigens was preserved only in LTNP. In contrast to HIV-specific CD8(+) T-cell responses of LTNP, HLA B5701-restricted responses within CMV pp65 were rare and did not dominate the total CMV-specific response. Virus-specific CD8(+) T cells were predominantly CD27(+)45RO(+) for HIV and CD27(-)45RA(+) for CMV; however, these phenotypes were highly variable and heavily influenced by the degree of viremia. Although IL-2 induced significant expansions of CMV-specific CD8(+) T cells in LTNP and progressors by increasing both the numbers of cells entering the proliferating pool and the number of divisions, the proliferative capacity of a significant proportion of HIV-specific CD8(+) T cells was not restored with exogenous IL-2. These results suggest that immunodominance by HLA B5701-restricted cells is specific to HIV infection in LTNP and is not a feature of responses to other chronic viral infections. They also suggest that poor responsiveness to IL-2 is a property of HIV-specific CD8(+) T cells of progressors that is not shared with responses to other viruses over which immunologic control is maintained.

  View details for DOI 10.1128/JVI.02128-08

  View details for Web of Science ID 000263650500032

  View details for PubMedID 19129459

• Monitoring antimalarial safety and tolerability in clinical trials: A case study from Uganda MALARIA JOURNAL Staedke, S. G., Jagannathan, P., Yeka, A., Bukirwa, H., Banek, K., Maiteki-Sebuguzi, C., Clark, T. D., Nzarubara, B., Njama-Meya, D., Mpimbaza, A., Rosenthal, P. J., Kamya, M. R., Wabwire-Mangen, F., Dorsey, G., Talisuna, A. O. 2008; 7

  Abstract

  New antimalarial regimens, including artemisinin-based combination therapies (ACTs), have been adopted widely as first-line treatment for uncomplicated malaria. Although these drugs appear to be safe and well-tolerated, experience with their use in Africa is limited and continued assessment of safety is a priority. However, no standardized guidelines for evaluating drug safety and tolerability in malaria studies exist. A system for monitoring adverse events in antimalarial trials conducted in Uganda was developed. Here the reporting system is described, and difficulties faced in analysing and interpreting the safety results are illustrated, using data from the trials.Between 2002 and 2007, eleven randomized, controlled clinical trials were conducted to compare the efficacy, safety, and tolerability of different antimalarial regimens for treatment of uncomplicated malaria in Uganda. The approach to adverse event monitoring was similar in all studies. A total of 5,614 treatments were evaluated in 4,876 patients. Differences in baseline characteristics and patterns of adverse event reporting were noted between the sites, which limited the ability to pool and analyse data. Clinical failure following antimalarial treatment confounded associations between treatment and adverse events that were also common symptoms of malaria, particularly in areas of lower transmission intensity.Despite prospectively evaluating for adverse events, limitations in the monitoring system were identified. New standardized guidelines for monitoring safety and tolerability in antimalarial trials are needed, which should address how to detect events of greatest importance, including serious events, those with a causal relationship to the treatment, those which impact on adherence, and events not previously reported.Although the World Health Organization has supported the development of pharmacovigilance systems in African countries deploying ACTs, additional guidance on adverse events monitoring in antimalarial clinical trials is needed, similar to the standardized recommendations available for assessment of drug efficacy.

  View details for DOI 10.1186/1475-2875-7-107

  View details for Web of Science ID 000257609000001

  View details for PubMedID 18547416

• Safety and tolerability of combination antimalarial therapies for uncomplicated falciparum malaria in Ugandan children MALARIA JOURNAL Maiteki-Sebuguzi, C., Jagannathan, P., Yau, V. M., Clark, T. D., Njama-Meya, D., Nzarubara, B., Talisuna, A. O., Kamya, M. R., Rosenthal, P. J., Dorsey, G., Staedke, S. G. 2008; 7

  Abstract

  Combination antimalarial therapy is recommended for the treatment of uncomplicated falciparum malaria in Africa; however, some concerns about the safety and tolerability of new regimens remain. This study compared the safety and tolerability of three combination antimalarial regimens in a cohort of Ugandan children.A longitudinal, single-blind, randomized clinical trial of children was conducted between November 2004 and May 2007 in Kampala, Uganda. Upon diagnosis of the first episode of uncomplicated malaria, participants were randomized to treatment with amodiaquine + sulphadoxine-pyrimethamine (AQ+SP), artesunate + amodiaquine (AS+AQ), or artemether-lumefantrine (AL). Once randomized, participants received the same regimen for all subsequent episodes of uncomplicated malaria. Participants were actively monitored for adverse events for the first 14 days after each treatment, and then passively followed until their next study medication treatment, or withdrawal from study. Outcome measures included the risk of adverse events at 14 and 42 days after treatment.Of 601 enrolled children, 382 were diagnosed with at least one episode of uncomplicated malaria and were treated with study medications. The median age at treatment was 6.3 years (range 1.1 - 12.3 years). At 14 days of follow-up, AQ+SP treatment was associated with a higher risk of anorexia, weakness, and subjective fever than treatment with AL, and a higher risk of weakness, and subjective fever than treatment with AS+AQ. Treatment with AL was associated with a higher risk of elevated temperature. Repeated episodes of neutropaenia associated with AS+AQ were detected in one participant. Considering only children less than five years, those who received AQ+SP were at higher risk of developing moderate or severe anorexia and weakness than those treated with AL (anorexia: RR 3.82, 95% CI 1.59 - 9.17; weakness: RR 5.40, 95% CI 1.86 - 15.7), or AS+AQ (anorexia: RR 2.10, 95% CI 1.04 - 4.23; weakness: RR 2.26, 95% CI 1.01 - 5.05). Extending the analysis to 42 days of follow-up had little impact on the findings.This study confirms the safety and tolerability of AS+AQ and AL in Ugandan children, and suggests that AQ+SP is safe, but less well-tolerated, particularly in younger children. As newer antimalarial regimens are deployed, collecting data on their safety and tolerability will be essential.Current Controlled Trials Identifier ISRCTN37517549.

  View details for DOI 10.1186/1475-2875-7-106

  View details for Web of Science ID 000257163700001

  View details for PubMedID 18547415

• Limitations in knowledge of HIV transmission among HIV-positive patients accessing case management services in a resource-poor setting AIDS CARE-PSYCHOLOGICAL AND SOCIO-MEDICAL ASPECTS OF AIDS/HIV Fawzi, M. C., Jagannathan, P., Cabral, J., Banares, R., Salazar, J., Farmer, P., BEHFOROUZ, H. 2006; 18 (7): 764-771

  Abstract

  HIV has increasingly become an infection of poverty. Adequate HIV transmission knowledge among HIV-positive patients is necessary to reduce the risk of secondary infection and protect those who are uninfected from transmission. This study was conducted among individuals enrolled in a program that serves impoverished HIV patients in the Boston area. Although the mean HIV transmission knowledge score was 80% for this group, a significant proportion of patients demonstrated limitations in knowledge of HIV transmission. Highly vulnerable patients, such as those who reported not accessing HIV medications, a history of sexual abuse, or problems getting clothing, had lower levels of HIV knowledge. This paper hopes to alert providers that their most vulnerable patients may be at an increased risk of re-infection or transmission due to limited HIV knowledge. Programs that serve HIV-positive patients coping with poverty and other serious problems need to ensure adequate knowledge of HIV transmission to reduce the overall burden of HIV in resource-poor settings.

  View details for DOI 10.1080/09540120500373844

  View details for Web of Science ID 000240620300017

  View details for PubMedID 16971286