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![Iron deficiency (ID) is associated with lower proportion of visits with hyperparasitemia (A) and severe malaria (B). Iron status measures were obtained at both routine and hospital visits. (A) Percentage of visits with hyperparasitemia in different age groups stratified by iron status. (B) Percentage of visits with severe malaria in different age groups stratified by iron status. Children with ID had a 24.0-fold lower odds of hyperparasitemia (odds ratio [OR; 95% confidence interval; CI] = 0.04 [0.02, 0.07], P < .001) and a 4.0-fold lower odds of severe malaria (OR [95% CI] 0.25 [0.14, 0.46], P < .001) than children with normal iron status, even after adjusting for potential confounders. Visits with normal iron stores (black bars) and ID (white bars) are shown. Samples sizes for visits with normal iron stores are given above samples sizes with ID. Error bars represent 95% CIs.](profile/Moses-Gwamaka/publication/221851732/figure/fig3/AS:324862825517110@1454464741473/ron-deficiency-ID-is-associated-with-lower-proportion-of-visits-with-hyperparasitemia.png)
Iron deficiency (ID) is associated with lower proportion of visits with hyperparasitemia (A) and severe malaria (B). Iron status measures were obtained at both routine and hospital visits. (A) Percentage of visits with hyperparasitemia in different age groups stratified by iron status. (B) Percentage of visits with severe malaria in different age groups stratified by iron status. Children with ID had a 24.0-fold lower odds of hyperparasitemia (odds ratio [OR; 95% confidence interval; CI] = 0.04 [0.02, 0.07], P < .001) and a 4.0-fold lower odds of severe malaria (OR [95% CI] 0.25 [0.14, 0.46], P < .001) than children with normal iron status, even after adjusting for potential confounders. Visits with normal iron stores (black bars) and ID (white bars) are shown. Samples sizes for visits with normal iron stores are given above samples sizes with ID. Error bars represent 95% CIs.
Source publication
Iron supplementation may increase malaria morbidity and mortality, but the effect of naturally occurring variation in iron status on malaria risk is not well studied.
A total of 785 Tanzanian children living in an area of intense malaria transmission were enrolled at birth, and intensively monitored for parasitemia and illness including malaria for...
Contexts in source publication
Context 1
... effect of ID to decrease hyperparasitemia risk became stronger with age (P 5 .005; Figure 3A). In addition, children with ID had a 4.0-fold lower odds of concurrent severe malaria compared with children who were iron-replete after adjusting for potential confounders (OR [95% CI] 0.25 [0.14, 0.46], P , .001; Figure 3B). ...
Context 2
... addition, children with ID had a 4.0-fold lower odds of concurrent severe malaria compared with children who were iron-replete after adjusting for potential confounders (OR [95% CI] 0.25 [0.14, 0.46], P , .001; Figure 3B). ...
Context 3
... we restricted our cross-sectional analyses of concurrent iron status and parasitemia to samples obtained during routine, nonsick visits (Figure 2). Third, we repeated our cross-sectional analyses of the impact of concur- rent iron status on parasitemia, hyperparasitemia, and severe malaria ( Figure 3) by using several secondary definitions of ID (see Supplementary Table 1). These alternative definitions of ID are reportedly less influenced by concurrent inflammation [15][16][17][18][19]31], and all demonstrated similar relationships with malaria risk. ...
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... Although several studies suggest that preventing and treating iron deficiency can reduce the incidence of infections [105], iron overload can increase the risk of morbidity. Therefore, iron supplementation should be carefully monitored or avoided [106]. ...
Recent insights into the influence of nutrition on immune system components have driven the development of dietary strategies targeting the prevention and management of major metabolic-inflammatory diseases. This review summarizes the bidirectional relationship between nutrition and immunocompetence, beginning with an overview of immune system components and their functions. It examines the effects of nutritional status, dietary patterns, and food bioactives on systemic inflammation, immune cell populations, and lymphoid tissues, as well as their associations with infectious and chronic disease pathogenesis. The mechanisms by which key nutrients influence immune constituents are delineated, focusing on vitamins A, D, E, C, and B, as well as minerals including zinc, iron, and selenium. Also highlighted are the immunomodulatory effects of polyunsaturated fatty acids as well as bioactive phenolic compounds and probiotics, given their expanding relevance. Each section addresses the implications of nutritional and nutraceutical interventions involving these nutrients within the broader context of major infectious, metabolic, and inflammatory diseases. This review further underscores that, while targeted nutrient supplementation can effectively restore immune function to optimal levels, caution is necessary in certain cases, as it may increase morbidity in specific diseases. In other instances, dietary counseling should be integrated to ensure that therapeutic goals are achieved safely and effectively.
... In α-Thalassemia, reduced synthesis of α-globin chains limits hemoglobin availability, interfering with parasite growth and development [26]. While in β-Thalassemia, excess α-chains precipitate within erythrocytes, hindering malaria parasite maturation and survival [27]. Recognizing the protective role of hemoglobinopathies informs genetic counseling efforts in endemic regions, allowing for informed reproductive choices and family planning [28]. ...
This work delves into the intricate dynamics between malaria and hematological disorders, with a particular focus on elucidating the interplay between epidemiological trends and blood cell alterations. By meticulously dissecting the existing literature, this study aims to elucidate the mechanisms through which malaria influences blood cell alterations and contributes to the development of various hematological complications. This review underscores the urgent need for a multidisciplinary approach that integrates epidemiology, hematology, and pathology to better understand this complex relationship. Furthermore, it systematically unravels the diverse hematological disorders that arise as sequelae of malaria infection, providing a comprehensive understanding of the epidemiological dimensions and consequences of these complications. Building upon this foundation, this study investigates the molecular connection between hemoglobinopathies and malaria susceptibility, exploring the protective effects conferred by certain genetic variants against severe malaria. Drawing upon existing epidemiological data and cutting-edge molecular analyses, this paper highlights novel avenues for malaria management and intervention strategies. The conclusions and future perspectives presented in this paper emphasize the imperative of an integrated approach that synthesizes epidemiological knowledge with molecular insights, ultimately advancing our ability to mitigate the burdens imposed by malaria and its associated hematological morbidities. By bridging the fields of epidemiology and hematology, this research contributes to the broader understanding of malaria pathogenesis and paves the way for enhanced diagnostic, therapeutic, and preventive measures in the fight against this global health threat.
... This finding aligned with that of Kamal and Ahmed8, who reported that serum Mg levels were significantly declined with increasing parasitaemia from low parasitaemia, moderate parasitaemia and high parasitaemia among Sudanese subjects with malaria infection. Conversely, the finding from this study did not agree with some other studies 29,30 . The authors reported lower levels of calcium in subjects with malaria infection. ...
... A study from Tanzania shown that iron deficiency may be protective against malaria infection and deaths in chil-dren hence risk of malaria infection may be influenced by physiologic status of iron 30 . An insignificant change in the level of iron between malaria infected young adults and controls was reported by these authors 17 . ...
Background/Objective: A high calcium-to-magnesium ratio above 2:1 has been associated with higher risk of metabolic, inflammation and cardiovascular disorders. This study evaluates the serum levels of iron, magnesium, calcium, folate, vitamin B12 and calcium to magnesium ratio in children with uncomplicated malaria infection. Materials and Methods: Measured nutritional parameters were determined in 300 children (100 males and 100 females) with malaria infection and 100 children (50 males and 50 females) without malaria infection using Enzyme linked Immunosorbent Assay and spectrophotometric methods. Results: Significantly lower (p<0.001) levels of serum magnesium, iron, vitamin B12, folate and Packed cell volume (p<0.03) were observed among children with malaria than controls. On the other hand, serum calcium (8.45±0.20) and calcium-to-magnesium ratio (3.9:1.0) (were significantly higher (p<0.001) in malaria infected children than controls. Calcium to magnesium ratio correlated (r=0.188; p<0.01) with malaria parasitaemia. Conclusion: Higher serum calcium-to-magnesium ratio above the recommended 2.1 may contribute to increase risk of morbidity and mortality. Nutritional intervention aimed at lowering the ca/mg ratio may be essential in the management of malaria infection in Children. Keywords: Child; calcium; magnesium; parasites.
... Iron deficiency has been shown to protect against clinical malaria in African children 1 and pregnant women, 2 and in African children protects against severe malaria and death. 3 Furthermore, iron supplementation has been associated with subsequent malaria infection and mortality. 4 These clinical studies are supported by in vitro data demonstrating that P. falciparum infects irondeficient erythrocytes less efficiently, and that this effect is reversed by iron supplementation. ...
... Previous studies have demonstrated that iron deficiency is associated with a reduced risk of malaria in African children 1 and pregnant women, 34,35 and that iron supplementation increases risk of malaria infection and mortality. 3 Furthermore, in vitro studies of parasite growth in red blood cells (RBCs) from iron replete donors have demonstrated increased parasite growth, 5 and a modelling study has suggested an association between host iron bioavailability and parasite multiplication rate. 36 In contrast to these studies, in the current study where parasite growth rates were evaluated in 55 experimentally infected volunteers, we did not find any correlation between any of the iron parameters at baseline with either peak parasitaemia, total pretreatment parasite burden, or parasite multiplication rate. ...
Background
The interaction between iron status and malaria is incompletely understood. We evaluated longitudinal changes in iron homeostasis in volunteers enrolled in malaria volunteer infection studies (VIS) and in Malaysian patients with falciparum and vivax malaria.
Methods
We retrieved data and samples from 55 participants (19 female) enrolled in malaria VIS, and 171 patients (45 female) with malaria and 30 healthy controls (13 female) enrolled in clinical studies in Malaysia. Ferritin, hepcidin, erythropoietin, and soluble transferrin receptor (sTfR) were measured by ELISA.
Findings
In the VIS, participants’ parasitaemia was correlated with baseline mean corpuscular volume (MCV), but not iron status (ferritin, hepcidin or sTfR). Ferritin, hepcidin and sTfR all increased during the VIS. Ferritin and hepcidin normalised by day 28, while sTfR remained elevated. In VIS participants, baseline ferritin was associated with post-treatment increases in liver transaminase levels. In Malaysian patients with malaria, hepcidin and ferritin were elevated on admission compared to healthy controls, while sTfR increased following admission. By day 28, hepcidin had normalised; however, ferritin and sTfR both remained elevated.
Interpretation
Our findings demonstrate that parasitaemia is associated with an individual's MCV rather than iron status. The persistent elevation in sTfR 4 weeks post-infection in both malaria VIS and clinical malaria may reflect a causal link between malaria and iron deficiency.
Funding
10.13039/501100000925National Health and Medical Research Council (Program Grant 1037304, Project Grants 1045156 and 1156809; Investigator Grants 2016792 to BEB, 2016396 to JCM, 2017436 to MJG); US National Institute of Health (R01-AI116472-03); Malaysian 10.13039/100009647Ministry of Health (BP00500420).
... The conventional knowledge that iron deficiency, which often manifests as low MCV, is somewhat protective against malaria infection [29][30][31] supports the finding of this study. Iron deficiency anaemia, low MCV, and sickle cell disease, have been found to be evolutionary protective mechanisms against malaria, seen mostly in people of African descent where malaria is endemic [30]. ...
... A study in Ghana discovered lower MCV values among children in areas of low malaria transmission intensity compared to areas of higher transmission intensity [32]. The Plasmodium parasite requires iron for its asexual proliferation in humans, and it can get this from RBCs with adequate HB, as seen in normal MCV [29][30][31]. Iron supplementation has also been reported, to worsen the severity of malaria [29,31]. ...
... The Plasmodium parasite requires iron for its asexual proliferation in humans, and it can get this from RBCs with adequate HB, as seen in normal MCV [29][30][31]. Iron supplementation has also been reported, to worsen the severity of malaria [29,31]. ...
Background
Although, several studies have reported abnormal Mean Corpuscular Volume (MCV) values and anaemia associated with malaria infections with a focus on Plasmodium falciparum among patients with complicated and uncomplicated malaria, none has looked at the association with asymptomatic malaria. This study aimed to assess this association.
Methods
We conducted a cross-sectional study using 3 mL of blood samples from 549 children aged 5–17 years attending 5 schools selected in the Volta Region. Semi-structured questionnaires were administered to the children to obtain demographic data. Blood samples were collected to estimate the children's full blood count (FBC) and malaria status. Data obtained were analysed using STATA 15 software. P-values of less than 0.05 were considered statistically significant.
Results
Most of the children in this study (49.9%) had normal MCV (81.3–91.3 fL) with an overall malaria prevalence of 55.6 % (95% CI: 51.3–59.8) and anaemia prevalence of 48.6% (95% CI 44.4–52.9). Most anaemic children had normal MCV (81.3–91.3 fL) (49.8, 95% CI 43.7–56.0). The predicted probability of malaria was highly likely among children with normal MCV (81.3–91.3 fL) but with high variability and uncertainty among those with low MCV (<81.3 fL) and high MCV (>91.3 fL).
Conclusion
This study shows a reduced predicted probability of malaria among children with low and high MCV, playing a protective function against malaria. Further studies are required to elucidate the interaction.
... Sexual and asexual parasites in red blood cells were counted by examining Giemsa-stained thick smears by 1000× oil immersion light microscopy until a total of 200 leucocytes (white blood cells (WBCs)) had been observed (Owusu-Agyei et al., 2001;Gwamaka et al., 2012). To convert the number of parasites observed to a count per microlitre (par μL −1 ) the number observed was multiplied by the actual leucocyte numbers per μL blood and divided by 200 when contemporaneous haematology data were available (Sumbele et al., 2015;Raja et al., 2020). ...
Naturally acquired immunity to the different types of malaria in humans occurs in areas of endemic transmission and results in asymptomatic infection of peripheral blood. The current study examined the possibility of naturally acquired immunity in Bornean orangutans, Pongo pygmaeus, exposed to endemic Plasmodium pitheci malaria. A total of 2140 peripheral blood samples were collected between January 2017 and December 2022 from a cohort of 135 orangutans housed at a natural forested Rescue and Rehabilitation Centre in West Kalimantan, Indonesia. Each individual was observed for an average of 4.3 years during the study period. Blood samples were examined by microscopy and polymerase chain reaction for the presence of plasmodial parasites. Infection rates and parasitaemia levels were measured among age groups and all 20 documented clinical malaria cases were reviewed to estimate the incidence of illness and risk ratios among age groups. A case group of all 17 individuals that had experienced clinical malaria and a control group of 34 individuals having an event of >2000 parasites μL⁻¹ blood but with no outward or clinical sign of illness were studied. Immature orangutans had higher-grade and more frequent parasitaemia events, but mature individuals were more likely to suffer from clinical malaria than juveniles. The case orangutans having patent clinical malaria were 256 times more likely to have had no parasitaemia event in the prior year relative to asymptomatic control orangutans. The findings are consistent with rapidly acquired immunity to P. pitheci illness among orangutans that wanes without re-exposure to the pathogen.
... Iron deficiency has been shown to protect against clinical malaria in African children 1 and pregnant women, 2 and in African children protects against severe malaria and death. 3 Furthermore, iron supplementation has been associated with subsequent malaria infection and mortality. 4 These clinical studies are supported by in vitro data demonstrating that P. ...
... Indeed, previous studies have demonstrated that iron deficiency is associated with a reduced risk of malaria in African children 1 and pregnant women, 34,35 and that iron supplementation increases risk of malaria infection and mortality. 3 Furthermore, in vitro studies of parasite growth in red blood cells (RBCs) from iron replete donors have demonstrated increased parasite growth, 5 and a modelling study has suggested an association between host iron bioavailability and parasite multiplication rate. 36 In contrast to these studies, in the current study where parasite growth rates were evaluated in 55 experimentally infected volunteers, we did not find any correlation between any of the iron parameters at baseline with either peak parasitaemia, total pre-treatment parasite burden, or parasite multiplication rate. ...
Background
The interaction between iron deficiency and malaria is incompletely understood. We evaluated longitudinal changes in iron homeostasis in volunteers enrolled in malaria volunteer infection studies (VIS) and in Malaysian patients with falciparum and vivax malaria.
Methods
We retrieved samples and associated data from 55 participants enrolled in malaria VIS, and 171 malaria patients and 30 healthy controls enrolled in clinical studies in Malaysia. Ferritin, hepcidin, erythropoietin, and soluble transferrin receptor (sTfR) were measured by ELISA.
Results
In the VIS, participants' parasitaemia was correlated with baseline mean corpuscular volume (MCV), but not iron status (ferritin, hepcidin or sTfR). Ferritin, hepcidin and sTfR all increased during the VIS. Ferritin and hepcidin normalised by day 28, while sTfR remained elevated. In VIS participants, baseline iron status (ferritin) was associated with post-treatment increases in liver transaminase levels. In Malaysian malaria patients, hepcidin and ferritin were elevated on admission compared to healthy controls, while sTfR increased following admission. Hepcidin normalised by day 28; however, ferritin and sTfR both remained elevated 4 weeks following admission.
Conclusion
Our findings demonstrate that parasitaemia is associated with an individual's MCV rather than iron status. The persistent elevation in sTfR 4 weeks post-infection in both malaria VIS and clinical malaria may reflect a causal link between malaria and iron deficiency.
... During the asexual stage, malaria parasites infect hepatocytes or red blood cells and uptake iron from the host for their growth and amplification. Changes in the host iron status will affect the iron availability for the parasites [9][10][11]. Studies on murine malaria models have uncovered that secondary liver infections are unlikely to happen even when a tiny amount of malaria parasites exists in the blood [12]. ...
Background
The rapid reproduction of malaria parasites requires proper iron uptake. However, the process of iron absorption by parasites is rarely studied. Divalent metal transporter (DMT1) is a critical iron transporter responsible for uptaking iron. A homolog of human DMT1 exists in the malaria parasite genome, which in Plasmodium yoelii is hereafter named PyDMT1.
Results
PyDMT1 knockout appears to be lethal. Surprisingly, despite dwelling in an iron-rich environment, the parasite cannot afford to lose even partial expression of PyDMT1; PyDMT1 hypomorphs were associated with severe growth defects and quick loss of pathogenicity. Iron supplementation could completely suppress the defect of the PyDMT1 hypomorph during in vitro culturing. Genetic manipulation through host ferritin (Fth1) knockout to increase intracellular iron levels enforced significant growth inhibition in vivo on the normal parasites but not the mutant. In vitro culturing with isolated ferritin knockout mouse erythrocytes completely rescued PyDMT1-hypomorph parasites.
Conclusion
A critical iron requirement of malaria parasites at the blood stage as mediated by this newly identified iron importer PyDMT1, and the iron homeostasis in malarial parasites is finely tuned. Tipping the iron balance between the parasite and host will efficiently kill the pathogenicity of the parasite. Lastly, PyDMT1 hypomorph parasites were less sensitive to the action of artemisinin.
... Addressing iron deficiency through population-based iron supplementation programs has been frustrated by serious side effects of inorganic forms of iron which, due to low enteric absorption, must be given in relatively high levels (1). Those effects include gut inflammation (2)(3)(4)(5), changes in the gut microbiome (4,5), bloody diarrhea (2, 5-7); among iron-replete children in malaria-endemic areas increased serious morbidity has been reported (8)(9)(10)(11)(12)(13)(14)(15). These effects are thought to involve stress on the gut by unabsorbed iron, which can be pro-oxidative and pro-inflammatory, favoring the proliferation of pathogenic enteric bacteria (14),and contributing to inflammatory responses (2,5,16,17) that lead to down-regulation of iron absorption (18). ...
Introduction
The safety of novel forms of iron in healthy, iron-replete adults as might occur if used in population-based iron supplementation programs was examined. We tested the hypotheses that supplementation with nanoparticulate iron hydroxide adipate tartrate (IHAT), an iron-enriched Aspergillus oryzae product (ASP), or ferrous sulphate heptahydrate (FS) are safe as indicated by erythrocyte susceptibility to malarial infection, bacterial proliferation, and gut inflammation. Responses to FS administered daily or weekly, and with or without other micronutrients were compared.
Methods
Two phases of randomized, double-blinded trials were conducted in Boston, MA. Phase I randomized 160 volunteers to six treatments: placebo, IHAT, ASP, FS, and FS plus a micronutrient powder (MNP) administrated daily at 60 mg Fe/day; and FS administered as a single weekly dose of 420 mg Fe. Phase II randomized 86 volunteers to IHAT, ASP, or FS administered at 120 mg Fe/day. Completing these phases were 151 and 77 participants, respectively. The study was powered to detect effects on primary endpoints: susceptibility of participant erythrocytes to infection by Plasmodium falciparum, the proliferation potential of selected pathogenic bacteria in sera, and markers of gut inflammation. Secondary endpoints for which the study was not powered included indicators of iron status and gastrointestinal symptoms.
Results
Supplementation with any form of iron did not affect any primary endpoint. Regarding secondary endpoints, in Phase I participants taking IHAT more frequently reported abdominal pain (27%, p = 0.008) than other iron forms; those taking the weekly FS dose more frequently reported nausea (20%, p = 0.009) than the other forms and modes of administration. In phase II, no such differences were observed.
Discussion
With respect to the primary endpoints, few differences were found when comparing these forms of iron, indicating that 28 days of 60 or 120 mg/day of IHAT, ASP, or FS may be safe for healthy, iron-replete adults. With respect to other endpoints, subjects receiving IHAT more frequently reported abdominal pain and nausea, suggesting the need for further study.
Clinical Trial Registration
ClinicalTrials.gov, NCT03212677; registered: 11 July 2017.
... Despite the importance of iron, iron deficiency is exceedingly common in humans, and iron deficiency anaemia is estimated to affect a sixth of the world's population [5,6]. In the context of human malaria infection, iron deficiency can decrease the risk of disease, severe disease, and mortality [7][8][9]. The protective effect of iron deficiency is at least partly mediated by anaemia, as RBCs isolated from anaemic individuals are less amenable to malaria parasite growth [10]. ...
... Iron deficiency impacts malaria infection in humans [7][8][9], but beyond the effects of anaemia [10], little is known about how host iron deficiency influences malaria infection. Here we investigated how restricted cellular iron acquisition influenced P. chabaudi infection in mice. ...
... and fed standard chow containing 188 ppm iron (SDS Dietex Services, diet 801161) ad-libitum. Age-matched, [8][9][10][11][12][13] week-old female mice were used for experiments. Females were exclusively utilised to prevent loss of animals due to fighting, and to minimise the risk of severe adverse events from P. chabaudi infection, which is higher in males [85]. ...
Malaria and iron deficiency are major global health problems with extensive epidemiological overlap. Iron deficiency-induced anaemia can protect the host from malaria by limiting parasite growth. On the other hand, iron deficiency can significantly disrupt immune cell function. However, the impact of host cell iron scarcity beyond anaemia remains elusive in malaria. To address this, we employed a transgenic mouse model carrying a mutation in the transferrin receptor (TfrcY20H/Y20H), which limits the ability of cells to internalise iron from plasma. At homeostasis TfrcY20H/Y20H mice appear healthy and are not anaemic. However, TfrcY20H/Y20H mice infected with Plasmodium chabaudi chabaudi AS showed significantly higher peak parasitaemia and body weight loss. We found that TfrcY20H/Y20H mice displayed a similar trajectory of malaria-induced anaemia as wild-type mice, and elevated circulating iron did not increase peak parasitaemia. Instead, P. chabaudi infected TfrcY20H/Y20H mice had an impaired innate and adaptive immune response, marked by decreased cell proliferation and cytokine production. Moreover, we demonstrated that these immune cell impairments were cell-intrinsic, as ex vivo iron supplementation fully recovered CD4⁺ T cell and B cell function. Despite the inhibited immune response and increased parasitaemia, TfrcY20H/Y20H mice displayed mitigated liver damage, characterised by decreased parasite sequestration in the liver and an attenuated hepatic immune response. Together, these results show that host cell iron scarcity inhibits the immune response but prevents excessive hepatic tissue damage during malaria infection. These divergent effects shed light on the role of iron in the complex balance between protection and pathology in malaria.
