Cytokine network in adults with falciparum Malaria and HIV-1: increased IL-8 and IP-10 levels are associated with disease severity

Abstract

Background: Co-infection with malaria and HIV increases the severity and mortality of both diseases, but the cytokine responses related to this co-infection are only partially characterised. The aim of this study was to explore cytokine responses in relation to severity and mortality in malaria patients with and without HIV co-infection.

Methods: This was a prospective cross-sectional study. Clinical data and blood samples were collected from adults in Mozambique. Plasma was analysed for 21 classical pro- and anti-inflammatory cytokines, including interleukins, interferons, and chemokines.

Results: We included 212 in-patients with fever and/or suspected malaria and 56 healthy controls. Falciparum malaria was diagnosed in 131 patients, of whom 70 were co-infected with HIV-1. The malaria patients had marked increases in their cytokine responses compared with the healthy controls. Some of these changes, particularly interleukin 8 (IL-8) and interferon-γ-inducing protein 10 (IP-10) were strongly associated with falciparum malaria and disease severity. Both these chemokines were markedly increased in patients with falciparum malaria as compared with healthy controls, and raised levels of IL-8 and IP-10 were associated with increased disease severity, even after adjusting for relevant confounders. For IL-8, particularly high levels were found in malaria patients that were co-infected with HIV and in those who died during hospitalization.

Interpretations: Our findings underscore the complex role of inflammation during infection with P. falciparum, and suggest a potential pathogenic role for IL-8 and IP-10. However, the correlations do not necessarily mean any causal relationship, and further both clinical and mechanistic research is necessary to elucidate the role of cytokines in pathogenesis and protection during falciparum malaria.

Figure 1. Study population, flow diagram.

The focused sub-populations are encircled. Description of study population .

Figure 2. Circulating levels of IL-8 and IP-10 in adult falciparum malaria patients according to malaria severity.

Circulating levels of IL-8 (A) and IP-10 (B) in adult malaria patients with increasing severity. HC = Healthy controls; n = 52, UCM =  uncomplicated malaria n = 45, SM =  severe malaria n = 84. Missing data one patient in each group of patients. Levels of mediators are presented as boxplots; the box shows the interquartile range, the line through the box is the median, and the whiskers indicate the 10^th and the 90^th percentiles. *p = 0.04, **p = 0.002, ***p<0.001, ****p = 0.001 (Mann-Whitney test).