Seroprevalence of HTLV-1 and 2 amongst mothers and children in Malawi within the context of a systematic review and meta-analysis of HTLV seroprevalence in Africa

OBJECTIVES: Human T lymphotropic virus (HTLV)-1 causes T cell leukaemia and myelopathy. Together with HTLV-2 it is endemic in some African nations. Sero- prevalence data from Malawi are scarce, with no reports on associated disease incidence. HTLV seroprevalence and type were tested in 418 healthy mothers from Malawi. In addition, we tested the sera of 534 children to investigate mother-to-child transmission. To provide context, we conducted a systematic review and meta-analysis of HTLV seroprevalence in African women and children. METHODS: Stored samples from a previous childhood cancer and BBV study were analysed. ELISA was used for HTLV screening followed by immunoblot for confirmation and typing. Standard methods were used for the systematic review. RESULTS: HTLV seroprevalence was 2.6% (11/418) in mothers and 2.2% (12/534) in children. Three mothers carried HTLV-1 alone, seven had HTLV-2 and one was dually infected. Three children carried HTLV-1 alone, seven had HTLV-2 and two were dually infected. Only two corresponding mothers of the 12 HTLV positive children were HTLV positive. The systematic review included 66 studies of women and 13 of children conducted in 25 African countries. Seroprevalence of HTLV-1 varied from 0-17% and of HTLV-2 from 0-4%. CONCLUSIONS: In contrast to findings from other studies in Africa, the seroprevalence of HTLV-2 was higher than that of HTLV-1 in Malawi and one of the highest for the African region. The lack of mother-child concordance suggests alternative sources of infection among children. Our data and analyses contribute to HTLV prevalence mapping in Africa. This article is protected by copyright. All rights reserved

Assessment of mixed plasmodium falciparum sera5 infection in endemic burkitt lymphoma : A case-control study in Malawi

Background: Endemic Burkitt lymphoma (eBL) is the most common childhood cancer in Africa and is linked to Plasmodium falciparum (Pf) malaria infection, one of the most common and deadly childhood infections in Africa; however, the role of Pf genetic diversity is unclear. A potential role of Pf genetic diversity in eBL has been suggested by a correlation of age-specific patterns of eBL with the complexity of Pf infection in Ghana, Uganda, and Tanzania, as well as a finding of significantly higher Pf genetic diversity, based on a sensitive molecular barcode assay, in eBL cases than matched controls in Malawi. We examined this hypothesis by measuring diversity in Pf-serine repeat antigen-5 (Pfsera5), an antigenic target of blood-stage immunity to malaria, among 200 eBL cases and 140 controls, all Pf polymerase chain reaction (PCR)-positive, in Malawi. Methods: We performed Pfsera5 PCR and sequencing (~3.3 kb over exons II–IV) to determine single or mixed PfSERA5 infection status. The patterns of Pfsera5 PCR positivity, mixed infection, sequence variants, and haplotypes among eBL cases, controls, and combined/pooled were analyzed using frequency tables. The association of mixed Pfsera5 infection with eBL was evaluated using logistic regression, controlling for age, sex, and previously measured Pf genetic diversity. Results: Pfsera5 PCR was positive in 108 eBL cases and 70 controls. Mixed PfSERA5 infection was detected in 41.7% of eBL cases versus 24.3% of controls; the odds ratio (OR) was 2.18, and the 95% confidence interval (CI) was 1.12–4.26, which remained significant in adjusted results (adjusted odds ratio [aOR] of 2.40, 95% CI of 1.11–5.17). A total of 29 nucleotide variations and 96 haplotypes were identified, but these were unrelated to eBL. Conclusions: Our results increase the evidence supporting the hypothesis that infection with mixed Pf infection is increased with eBL and suggest that measuring Pf genetic diversity may provide new insights into the role of Pf infection in eBL

Impact of infection with human immunodeficiency virus-1 (HIV) on the risk of cancer among children in Malawi - preliminary findings

<p>Abstract</p> <p>Background</p> <p>The impact of infection with HIV on the risk of cancer in children is uncertain, particularly for those living in sub-Saharan Africa. In an ongoing study in a paediatric oncology centre in Malawi, children (aged ≤ 15 years) with known or suspected cancers are being recruited and tested for HIV and their mothers or carers interviewed. This study reports findings for children recruited between 2005 and 2008.</p> <p>Methods</p> <p>Only children with a cancer diagnosis were included. Odds ratios (OR) for being HIV positive were estimated for each cancer type (with adjustment for age (<5 years, ≥ 5 years) and sex) using children with other cancers and non-malignant conditions as a comparison group (excluding the known HIV-associated cancers, Kaposi sarcoma and lymphomas, as well as children with other haematological malignancies or with confirmed non-cancer diagnoses).</p> <p>Results</p> <p>Of the 586 children recruited, 541 (92%) met the inclusion criteria and 525 (97%) were tested for HIV. Overall HIV seroprevalence was 10%. Infection with HIV was associated with Kaposi sarcoma (29 cases; OR = 93.5, 95% CI 26.9 to 324.4) and with non-Burkitt, non-Hodgkin lymphoma (33 cases; OR = 4.4, 95% CI 1.1 to 17.9) but not with Burkitt lymphoma (269 cases; OR = 2.2, 95% CI 0.8 to 6.4).</p> <p>Conclusions</p> <p>In this study, only Kaposi sarcoma and non-Burkitt, non-Hodgkin lymphoma were associated with HIV infection. The endemic form of Burkitt lymphoma, which is relatively frequent in Malawi, was not significantly associated with HIV. While the relatively small numbers of children with other cancers, together with possible limitations of diagnostic testing may limit our conclusions, the findings may suggest differences in the pathogenesis of HIV-related malignancies in different parts of the world.</p

Assessment of the Combined Effect of Epstein-Barr Virus and Plasmodium falciparum Infections on Endemic Burkitt Lymphoma Using a Multiplex Serological Approach

Epstein–Barr virus (EBV) is a necessary cause of endemic Burkitt lymphoma (eBL), while the role of Plasmodium falciparum in eBL remains uncertain. This study aimed to generate new hypotheses on the interplay between both infections in the development of eBL by investigating the IgG and IgM profiles against several EBV and P. falciparum antigens. Serum samples collected in a childhood study in Malawi (2005–2006) from 442 HIV-seronegative children (271 eBL cases and 171 controls) between 1.4 and 15 years old were tested by quantitative suspension array technology against a newly developed multiplex panel combining 4 EBV antigens [Z Epstein–Barr replication activator protein (ZEBRA), early antigen-diffuse component (EA-D), EBV nuclear antigen 1, and viral capsid antigen p18 subunit (VCA-p18)] and 15 P. falciparum antigens selected for their immunogenicity, role in malaria pathogenesis, and presence in different parasite stages. Principal component analyses, multivariate logistic models, and elastic-net regressions were used. As expected, elevated levels of EBV IgG (especially against the lytic antigens ZEBRA, EA-D, and VCA-p18) were strongly associated with eBL [high vs low tertile odds ratio (OR) = 8.67, 95% confidence interval (CI) = 4.81–15.64]. Higher IgG responses to the merozoite surface protein 3 were observed in children with eBL compared with controls (OR = 1.29, 95% CI = 1.02–1.64), showing an additive interaction with EBV IgGs (OR = 10.6, 95% CI = 5.1–22.2, P = 0.05). Using elastic-net regression models, eBL serological profile was further characterized by lower IgM levels against P. falciparum preerythrocytic-stage antigen CelTOS and EBV lytic antigen VCA-p18 compared with controls. In a secondary analysis, abdominal Burkitt lymphoma had lower IgM to EBV and higher IgG to EA-D levels than cases with head involvement. Overall, this exploratory study confirmed the strong role of EBV in eBL and identified differential IgG and IgM patterns to erythrocytic vs preerythrocytic P. falciparum antigens that suggest a more persistent/chronic malaria exposure and a weaker IgM immune response in children with eBL compared with controls. Future studies should continue exploring how the malaria infection status and the immune response to P. falciparum interact with EBV infection in the development of eBL

Mosaic chromosomal alterations in peripheral blood leukocytes of children in sub-Saharan Africa

In high-income countries, mosaic chromosomal alterations in peripheral blood leukocytes are associated with an elevated risk of adverse health outcomes, including hematologic malignancies. We investigate mosaic chromosomal alterations in sub-Saharan Africa among 931 children with Burkitt lymphoma, an aggressive lymphoma commonly characterized by immunoglobulin-MYC chromosomal rearrangements, 3822 Burkitt lymphoma-free children, and 674 cancer-free men from Ghana. We find autosomal and X chromosome mosaic chromosomal alterations in 3.4% and 1.7% of Burkitt lymphoma-free children, and 8.4% and 3.7% of children with Burkitt lymphoma (P-values = 5.7×10-11 and 3.74×10-2, respectively). Autosomal mosaic chromosomal alterations are detected in 14.0% of Ghanaian men and increase with age. Mosaic chromosomal alterations in Burkitt lymphoma cases include gains on chromosomes 1q and 8, the latter spanning MYC, while mosaic chromosomal alterations in Burkitt lymphoma-free children include copy-neutral loss of heterozygosity on chromosomes 10, 14, and 16. Our results highlight mosaic chromosomal alterations in sub-Saharan African populations as a promising area of research

Human leukocyte antigen-DQA1*04:01 and rs2040406 variants are associated with elevated risk of childhood Burkitt lymphoma

Burkitt lymphoma (BL) is responsible for many childhood cancers in sub-Saharan Africa, where it is linked to recurrent or chronic infection by Epstein-Barr virus or Plasmodium falciparum. However, whether human leukocyte antigen (HLA) polymorphisms, which regulate immune response, are associated with BL has not been well investigated, which limits our understanding of BL etiology. Here we investigate this association among 4,645 children aged 0-15 years, 800 with BL, enrolled in Uganda, Tanzania, Kenya, and Malawi. HLA alleles are imputed with accuracy >90% for HLA class I and 85-89% for class II alleles. BL risk is elevated with HLA-DQA1*04:01 (adjusted odds ratio [OR] = 1.61, 95% confidence interval [CI] = 1.32-1.97, P = 3.71 × 10-6), with rs2040406(G) in HLA-DQA1 region (OR = 1.43, 95% CI = 1.26-1.63, P = 4.62 × 10-8), and with amino acid Gln at position 53 versus other variants in HLA-DQA1 (OR = 1.36, P = 2.06 × 10-6). The associations with HLA-DQA1*04:01 (OR = 1.29, P = 0.03) and rs2040406(G) (OR = 1.68, P = 0.019) persist in mutually adjusted models. The higher risk rs2040406(G) variant for BL is associated with decreased HLA-DQB1 expression in eQTLs in EBV transformed lymphocytes. Our results support the role of HLA variation in the etiology of BL and suggest that a promising area of research might be understanding the link between HLA variation and EBV control

Associations between Burkitt Lymphoma among Children in Malawi and Infection with HIV, EBV and Malaria: Results from a Case-Control Study

Background: Burkitt lymphoma, a childhood cancer common in parts of sub-Saharan Africa, has been associated with Epstein Barr Virus (EBV) and malaria, but its association with human immunodeficiency virus (HIV) is not clear.Methodology/Principal Findings: We conducted a case-control study of Burkitt lymphoma among children (aged <= 15 years) admitted to the pediatric oncology unit in Blantyre, Malawi between July 2005 and July 2006. Cases were 148 children diagnosed with Burkitt lymphoma and controls were 104 children admitted with non-malignant conditions or cancers other than hematological malignancies and Kaposi sarcoma. Interviews were conducted and serological samples tested for antibodies against HIV, EBV and malaria. Odds ratios for Burkitt lymphoma were estimated using unconditional logistic regression adjusting for sex, age, and residential district. Cases had a mean age of 7.1 years and 60% were male. Cases were more likely than controls to be HIV positive (Odds ratio (OR)) = 12.4, 95% Confidence Interval (CI) 1.3 to 116.2, p = 0.03). ORs for Burkitt lymphoma increased with increasing antibody titers against EBV (p = 0.001) and malaria (p = 0.01). Among HIV negative participants, cases were thirteen times more likely than controls to have raised levels of both EBV and malaria antibodies (OR = 13.2; 95% CI 3.8 to 46.6; p = 0.001). Reported use of mosquito nets was associated with a lower risk of Burkitt lymphoma (OR = 0.2, 95% CI, 0.03 to 0.9, p = 0.04).Conclusions: Our findings support prior evidence that EBV and malaria act jointly in the pathogenesis of Burkitt lymphoma, suggesting that malaria prevention may decrease the risk of Burkitt lymphoma. HIV may also play a role in the etiology of this childhood tumor

Infections and childhood cancer in Malawi

The causes of childhood cancers are not well understood. That infections are believed to play an important role in childhood cancer development is of particular interest in sub-Saharan Africa, where infectious diseases are common. The objectives of this thesis were to identify childhood cancers associated with HIV, malaria, EBV and HHV-8, and to investigate child and maternal factors associated with Burkitt lymphoma and Kaposi sarcoma.In Blantyre, Malawi, 305 children diagnosed with cancer and 212 of their mothers, were recruited. Risk factor data were collected using a brief questionnaire and blood samples tested for infections.Case-control analyses were conducted to compare 148 Burkitt lymphoma cases and 22 Kaposi sarcoma case with a control group comprising 104 children with cancers other than those known to be associated with HIV.The prevalence of HIV was 6% among children with Burkitt lymphoma and 2% in controls (OR=12.4, 95% CI 1.3 to 116.2). Tumour risk increased with increasing litres of antibodies against EBV and malaria. In comparison with those who had low titres against both EBV and malaria, the highest risk of Burkitt lymphoma was among those with high titres against both infections (OR=13.2, 95% CI 3.8 to 46.6). Reported use of mosquito nets was protective against Burkitt lymphoma.The prevalence of HIV was 81% among children with Kaposi sarcoma (OR=762.7, 95% CI 44 to 13376), and risk increased with increasing HHV-8 antibodies. Prevalence of infections was also examined among children with other cancer types and no associations were identified, although the number of cases was small. Few maternal factors were found to be associated with cancer in children.This research demonstrates that infections play a particularly important role in increasing the risk of Burkitt lymphoma and Kaposi sarcoma in children in sub- Saharan Africa. Prevention or early treatment of these infections may be vital in the control of childhood cancer.</p

Infections and childhood cancer in Malawi

The causes of childhood cancers are not well understood. That infections are believed to play an important role in childhood cancer development is of particular interest in sub-Saharan Africa, where infectious diseases are common. The objectives of this thesis were to identify childhood cancers associated with HIV, malaria, EBV and HHV-8, and to investigate child and maternal factors associated with Burkitt lymphoma and Kaposi sarcoma.In Blantyre, Malawi, 305 children diagnosed with cancer and 212 of their mothers, were recruited. Risk factor data were collected using a brief questionnaire and blood samples tested for infections.Case-control analyses were conducted to compare 148 Burkitt lymphoma cases and 22 Kaposi sarcoma case with a control group comprising 104 children with cancers other than those known to be associated with HIV.The prevalence of HIV was 6% among children with Burkitt lymphoma and 2% in controls (OR=12.4, 95% CI 1.3 to 116.2). Tumour risk increased with increasing litres of antibodies against EBV and malaria. In comparison with those who had low titres against both EBV and malaria, the highest risk of Burkitt lymphoma was among those with high titres against both infections (OR=13.2, 95% CI 3.8 to 46.6). Reported use of mosquito nets was protective against Burkitt lymphoma.The prevalence of HIV was 81% among children with Kaposi sarcoma (OR=762.7, 95% CI 44 to 13376), and risk increased with increasing HHV-8 antibodies. Prevalence of infections was also examined among children with other cancer types and no associations were identified, although the number of cases was small. Few maternal factors were found to be associated with cancer in children.This research demonstrates that infections play a particularly important role in increasing the risk of Burkitt lymphoma and Kaposi sarcoma in children in sub- Saharan Africa. Prevention or early treatment of these infections may be vital in the control of childhood cancer

Infections and childhood cancer in Malawi

The causes of childhood cancers are not well understood. That infections are believed to play an important role in childhood cancer development is of particular interest in sub-Saharan Africa, where infectious diseases are common. The objectives of this thesis were to identify childhood cancers associated with HIV, malaria, EBV and HHV-8, and to investigate child and maternal factors associated with Burkitt lymphoma and Kaposi sarcoma. In Blantyre, Malawi, 305 children diagnosed with cancer and 212 of their mothers, were recruited. Risk factor data were collected using a brief questionnaire and blood samples tested for infections. Case-control analyses were conducted to compare 148 Burkitt lymphoma cases and 22 Kaposi sarcoma case with a control group comprising 104 children with cancers other than those known to be associated with HIV. The prevalence of HIV was 6% among children with Burkitt lymphoma and 2% in controls (OR=12.4, 95% CI 1.3 to 116.2). Tumour risk increased with increasing litres of antibodies against EBV and malaria. In comparison with those who had low titres against both EBV and malaria, the highest risk of Burkitt lymphoma was among those with high titres against both infections (OR=13.2, 95% CI 3.8 to 46.6). Reported use of mosquito nets was protective against Burkitt lymphoma. The prevalence of HIV was 81% among children with Kaposi sarcoma (OR=762.7, 95% CI 44 to 13376), and risk increased with increasing HHV-8 antibodies. Prevalence of infections was also examined among children with other cancer types and no associations were identified, although the number of cases was small. Few maternal factors were found to be associated with cancer in children. This research demonstrates that infections play a particularly important role in increasing the risk of Burkitt lymphoma and Kaposi sarcoma in children in sub- Saharan Africa. Prevention or early treatment of these infections may be vital in the control of childhood cancer.EThOS - Electronic Theses Online ServiceGBUnited Kingdo