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Study of complex associations between severe malaria and malnutrition in pediatric age group

Open AccessPublished:May 17, 2022DOI:https://doi.org/10.1016/j.cegh.2022.101065

      Abstract

      Background

      In India, severe Malaria as well as malnutrition is quite prevalent in children. Till now, relationship between malnutrition and malaria remains inconclusive. Therefore, this study was carried out as an attempt to find relationship between severe malaria and malnutrition in pediatric age group.

      Materials and methods

      Study design was observational and was conducted in a tertiary care center in Uttar Pradesh. In age group of 6 month–18 years, total of 200 children suffering of severe malaria were included in study. Patients were classified into severe malaria as per WHO guidelines. Diagnosis and grading of malnutrition was done as per WHO guidelines for malnutrition.

      Results

      In age group of 0.5–5 years, comprising of 64 children with severe malaria, 56(87.5%) were malnourished while 8(12.5%) were well nourished. In age group of 5–18 years comprising of 136 cases of severe malaria, 103 (75.7%) were malnourished while 33 (24.3%) were well nourished. In 0.5–5 years of age group, all three species of malaria were found to be affecting malnourished children in higher percentage as compared to well nourished children.. However, in 5–18 years of age group, cases of P.vivax severe malaria were significantly higher in malnourished children.

      Conclusion

      This study showed higher percentage of malnourished children as compared to healthy children in cases of severe malaria and P.vivax cases with undernutrition to be significantly higher than other malarial parasites with undernutrition in 5–18 years age group. Therefore, malaria control strategies and nutritional intervention programmes should be consolidated together.

      Keywords

      1. Introduction

      Malaria and malnutrition co-exist in India and both independently are responsible for large proportion of morbidity and mortality in children.
      • Mahapatra A.
      • Mohapatra S.
      • Mitter N.
      • Dash S.S.
      • Mishra R.P.
      • Satapathy D.M.
      Malaria and malnutrition co-existence among underfive children of tribal dense regions of Odisha: a community based study.
      Malaria is endemic in India and many of South East Asia as well as other countries of world. In 2018, an estimated 228 million cases of malaria occurred worldwide, compared to 251 million cases in 2010
      • World Health Organization
      World Malaria Report.
      As of India, 0.43 million confirmed cases of malaria were reported by NVBDCP in 2018
      National vector borne disease control programme (NVBDCP). Malaria.
      Children aged below 5 years are the most vulnerable to severe malaria. This age group constitutes 67% of malaria death globally.
      UNICEF-WHO-World Bank
      Joint child malnutrition estimates.
      As per data of 2018, in less than five age group, wasted and severely wasted children was 49 and 17 million respectively.
      • Rayco-Solon P.
      • Moore S.E.
      • Fulford A.J.
      • Prentice A.M.
      Fifty-year mortality trends in three rural African villages.
      Due to heavy burden of both malaria and malnutrition in developing and developed countries, it's very important to understand how these two interact and influence each other. It has been well established that malaria adversely affects weight and height gain in children. However, what impact already existing under nutrition has on malaria is still not well understood and has been subject of controversy since early 1950. Few studies found increased risk of malaria in cases with underlying under nutrition
      • Deen J.L.
      • Walraven G.E.L.
      • von Seidlein L.
      Increased risk for malaria in chronically malnourished children under 5 years of age in rural Gambia.
      • Ehrhardt S.
      • Burchard G.D.
      • Mantel C.
      • et al.
      Malaria, anemia, and malnutrition in African children--defining intervention priorities.
      • Verhoef H.
      • West C.E.
      • Veenemans J.
      • Beguin Y.
      • Kok F.J.
      Stunting maydetermine the severity of malaria associated anemia in African children.
      While on contrary few studies found protective effect of malnutrition against malaria
      • Alexandre M.A.
      • Benzecry S.G.
      • Siqueira A.M.
      • et al.
      "The association between nutritional status and malaria in children from a rural community in the amazonian region: a longitudinal study.
      ,
      • Ferreira D.
      • Alexandre M.A.
      • Salinas J.L.
      • et al.
      “Association between anthropometry-based nutritional status and malaria: a systematic review of observational studies,”.
      ,
      • Shankar A.H.
      Nutritional modulation of malaria morbidity and mortality.
      . Other studies found no relationship between underlying malnutrition and risk of Malaria.
      • Muller O.
      • Garenne M.
      • Kouyate B.
      • Becher H.
      The association between protein-energy malnutrition, malaria morbidity and all-cause mortality inwest African children.
      Majority of such studies have been carried out in Africa where P.falciparum is predominant malarial species.
      As relation between malnutrition and malaria remains inconclusive and these two morbidities independently as well as with co-existence affect a large proportion of children in India, this study was undertaken.

      2. Material and methods

      A hospital based observational study was conducted in Pediatric ward of a Tertiary care hospital located in Kanpur, India. In age group of 6 months–18 years, 200 cases of severe malaria were included in study by convenient sampling. Written informed consent was taken from parents. Institutional ethical committee approved the study. Severe malaria was defined as per WHO guidelines.
      • WHO
      Severe and complicated malaria.
      Assessment of malnourishment was done by comparing child's weight and height to the standardised age- and sex-specific growth reference charts of WHO for children between 6 and 59 months of age (World Health Organization (WHO) Child Growth Standards 2006).
      Multicentre Growth Reference Study Group
      WHO Child Growth Standards: Length/height-For-Age, Weight-For-Age, Weight-For-Length, Weightfor- Height and Body Mass Index-For-Age: Methods and Development.
      The anthropometric indicators are expressed as a number of standard deviations (SDs) below or above the reference mean or median value, Z-score. Cutoffs of −3 were used to indicate severe malnutrition and values between −2 and −3 were considered to be moderate malnutrition. For children 5–18 years age group, Body Mass Index (BMI) < 5th centile for that age and gender in WHO BMI centiles chart was defined as undernutrition.
      Inclusion criteria:
      • 1.
        6month −18 years age group children
      • 2.
        Positive for malaria by peripheral blood smear (PBS) or card test and fulfilling criteria of severe malaria as per WHO guidelines.
      Exclusion criteria:
      • 1.
        Patient who tested negative for malaria on PBS or card test but were empirically treated for malaria on basis of presenting complaints and clinical features.
      • 2.
        Children with Tuberculosis, HIV, and acute or chronic diarrhoea, any other chronic illness that can cause malnutrition.

      3. Diagnosis

      Malaria was diagnosed by PBS and RMAT. Diagnosis of malaria and identification of species done by thin and thick blood smears respectively. Whereas, RMAT tests/card tests were based on detection of malarial antigens, Lactate dehydrogenase and histidine rich protein 2. RMAT or peripheral blood smear positive for both P. vivax and P. falciparum were labeled as mixed malarial infections.

      4. Data collection and analysis

      Data regarding patient clinical presentation, investigations and outcome were recorded. Prevalence of symptoms, signs, severity criteria were studied. Patient's age, gender and anthropometric measurements like weight, height, and weight for height were also recorded. Statistical significance of results was tested by appropriate statistical test like Chi square test/Fisher Exact test.

      5. Results

      In our study as shown in Table 1, Out of 64 children of severe malaria in 0.5–5 years age group 87.5% had moderate to severe PEM and 12.5% had normal nutritional status. While in 5–18 years of age group, out of total 136 cases of severe malaria, 33(24.2%) had normal nutrition while 103 (75.7%) were undernourished. We observed that percentage of cases with PEM/undernutrition was higher in comparison to children with normal nutritional status.
      Table 1Distribution of cases as per nutritional status in cases of severe malaria.
      Age groupNormal nutritionPEM/Undernutrition
      No.%No.%
      0.5–5 year (n = 64)812.5%5687.5%
      >5year (n = 136)3324.2%10375.7%
      Total(200)4120.5%15979.5%
      As shown in Table 2, out of 56 children with undernutrition in 0.5–5 year's age group, number of boys was 30. Whereas, in 5–18 years age group, out of total 159 cases of Undernutrition, 86 were boys. However, in both age group there was no statistically Significant difference in cases of severe malaria with malnutrition on basis of gender (p value = 0.92311, by chi-square).
      Table 2Distribution of undernourished children on the basis of gender in cases of severe malaria.
      Age groupCases with undernutritionBoysGirlsp value
      0.5–5 years (n = 64)5630260.923
      5–18 years (n = 136)1035647
      Total (200)1598673
      Further, as shown in Table 3, in 0.5–5 years of age group 40(88.9%) cases of P.vivax, 7 (87.5%) cases of P.falciparum and 9(81.8%) cases of mixed malaria had moderate to severe PEM. Thus all species of malaria were affecting malnourished children more than well nourished children. Not any species of malaria was found to be affecting malnourished children significantly higher than other species (p = 0.404).
      Table 3Distribution of cases as per malarial species and nutritional status in 0.5–5 years of age group (n = 64).
      Type of malariaNormal nutritionPEM (moderate and severe malnutrition)P value
      No.%No.%
      P.vivax (n = 45)511.14088.90.404
      P.falciparum (n = 8)112.5787.5
      Mixed malaria (n = 11)218.2981.8
      Total(n = 64)812.55687.5
      As mentioned in Table 4, Out of 136 cases of severe malaria in >5 years age group, 103 (75.7%) were undernourished which included 78(91.7%) cases of P.vivax, 9 (39.13%) cases of P.falciparum and 16 (57.14%) cases of Mixed malaria. We also found that undernutrition was significantly higher in P.vivax as compared to falciparum and mixed malaria (p = 0.00001).
      Table 4Distribution of cases as per malarial species and undernutrition in 5–18 years age group.
      Type of malariaNormal nutritionUndernutritionP value
      No.%No.%
      P.vivax(n = 85)78.27891.70.00001
      P.falciparum (n = 23)1460.9939.1
      Mixed malaria(n = 28)1242.31657.1
      Total(n = 136)3324.210375.7

      6. Discussion

      In our attempt to understand relation between malnutrition and severe malaria in pediatric age group, we found that percentage of malnourished children with severe malaria was higher than well nourished children with severe malaria in both age group of 0.5–5 years and 5–18 years.
      . Methodological dissimilarities and confounding factors can be responsible for variation in results of studies between malaria and malnutrition in modern era. These confounding factors include socioeconomic status, breastfeeding practices and other infectious diseases.
      • Muhangi L.
      • Lule S.A.
      • Mpairwe H.
      • et al.
      It has always been known that malnutrition predisposes to various infections. Then it also increases severity of those infections and attenuates body response to medicines. Malnutrition thus increases morbidity and mortality from any infection. On other hand, infection also lead to worsening of nutritional status, this leads to vicious cycle of malnutrition and increased severity of infection. Malnutrition adversely affects cellular as well as humoral immune response of body and complement activation. This suppressed immune response and lymphoid tissues atrophy of malnourished children leads to decreased host defence against malaria and increased susceptibility to occurrence and severity of malaria.
      • Fillol F.
      • Cournil A.
      • Boulanger D.
      • et al.
      Influence of wasting and stunting at the onset of the rainy season on subsequent malaria morbidity among rural preschool children in Senegal.
      Studies have shown decreased anti-malarial immune respondents and specific IgGAb in malnourished children as compared to healthy children.
      • Fillol F.
      • Cournil A.
      • Boulanger D.
      • et al.
      Influence of wasting and stunting at the onset of the rainy season on subsequent malaria morbidity among rural preschool children in Senegal.
      We further extended our study to find assosciation between malnutrition and type of malarial species. In 0.5–5 years of age group we found that percentage of all species of malaria was higher in malnourished children as compared to well nourished children. However there was no significant assosciation between malnutrition and type of malarial species. These results are in tune with study done to found assosciation between malaria and malnutrition in 0.5–5 years of age group in Southern Ethiopia.
      • Gone T.
      • Lemango F.
      • Eliso E.
      • et al.
      The association between malaria and malnutrition among under-five children in Shashogo District, Southern Ethiopia: a case-control study.
      As larger proportion of cases of malaria were malnourished, our results are also in favour of studies that found children infected with malaria to be at higher risk of malnutrition.
      • Galler J.R.
      • Barret L.R.
      Children and famine: long-term impact on development. Ambulatory and anaemia attributable to malariain Tanzanian children living under holoendemic conditions.
      We also analysed association between occurrence of severe malaria in undernourished and well-nourished children of 5–18 years of age group. In our study we found occurrence of P.vivax infections was significantly higher in malnourished children as compared to well-nourished children while P. falciparum and mixed malaria was found in both malnourished and well-nourished children without any statistically significant difference.
      Thus, P.vivax infection was significantly higher in malnourished children or P.vivax infection itself had been predisposing to malnutrition. Though effect of malnutrition on risk and severity of malaria remains controversial and contradictory, studies have already shown that malaria predisposes to malnutrition.
      • Nyakeriga A.M.
      • Troye-Blomberg M.
      • Chemtai A.K.
      • Marsh K.
      • Williams T.N.
      Malaria and nutritional status in children living on the coast of Kenya.
      • ter Kuile F.O.
      • Terlouw D.J.
      • Kariuki S.K.
      • et al.
      Impact of permethrin-treated bed nets on malaria, anemia, and growth in infants in an area of intense perennial malaria transmission in western Kenya.
      • ter Kuile F.O.
      • Terlouw D.J.
      • Phillips-Howard P.A.
      • et al.
      Impact of permethrin-treated bed nets on malaria and all-cause morbidity in young children in an area of intense perennial malaria transmission in western Kenya: cross-sectional survey.
      Only few studies have attempted to establish assosciation between P.vivax and malnutrition after elimination of as much of confounding factors as possible. These studies have found positive assosciation between exposure to P.vivax infection and risk of developing malnutrition.
      • Alexandre M.A.
      • Benzecry S.G.
      • Siqueira A.M.
      • et al.
      The Association between Nutritional status and malaria in children from a rural community in the Amazonian region: a longitudinal study.
      ,
      • Mueller I.
      • Galinski M.R.
      • Baird J.K.
      • et al.
      Key gaps in the knowledge of Plasmodium vivax, a neglected human malaria parasite.
      P.vivax infection has been proven to have chronic effect on growth and nutritional status.
      • Lee G.
      • Yori P.
      • Olortegui M.P.
      • et al.
      Comparative effects of vivax malaria, fever and diarrhoea on child growth.
      P vivax is also potent stimulator of pro-inflammatory cytokines and TNF-alpha; these pro-inflammatory mediators are responsible for anorexia and catabolic state thus contributing to malnutrition
      • Betuela I.
      • Rosanas-Urgell A.
      Kiniboro B Relapses contribute significantly to the risk of Plasmodium vivax infection and disease in Papua New Guinean children 1–5 years of age.
      P.vivax malaria unlike P.falciparum has unique ability to form hypnozoites in liver and stay in dormant form in body. These dormant hypnozoites then can cause multiple relapses after months of primary infection.
      • White M.T.
      • Walker P.
      • Karl S.
      • et al.
      Mathematical modelling of the impact of expanding levels of malaria control interventions on Plasmodium vivax.
      In endemic countries like India, these relapses are main cause of malaria than primary infection itself.
      • Baird J.K.
      • Hoffman S.L.
      Primaquine therapy for malaria.
      ,
      Primaquine is only drug that most effectively targets P.vivax hypnozoites.
      • Beutler B.
      • Milsark I.W.
      • Cerami A.C.
      Passive immunization against cachectin/tumor necrosis factor protects mice from lethal effect of endotoxin.
      However, Primaquine is known to cause hemolysis in G-6-P-D deficient individuals.
      In individuals with normal G-6-P-D levels and in areas with frequent relapsing P.vivax strains, WHO recommends supervised course of Primaquine at 0.5 mg/kg/day for 14 days.
      • ter Kuile F.O.
      • Terlouw D.J.
      • Kariuki S.K.
      • et al.
      Impact of permethrin-treated bed nets on malaria, anemia, and growth in infants in an area of intense perennial malaria transmission inwestern Kenya.
      However, because of limited lab facilities and economical constraints G-6-P-D levels are unavailable for most of malaria patients in endemic areas. These countries like India, recommend supervised lower dose of 0.25 mg/kg/day of Primaquine for 14 days. However, because of fear of hemolysis and lack of awareness amongst medical practitioner about crucial role of Primaquine in preventing relapses, even this low dose is not prescribed to malarial patients many a times. As daily supervision is also not feasible in most of health set-ups, patients are discharged on 14 days course of Primaquine. However, very often this course remains incomplete because of poor patient compliance. All these factors lead to persistence of hypnozoites and subsequently multiple malarial relapses in P.vivax infected patients. Multiple episodes of malaria predispose patients to malnutrition.
      . Thus our study emphasizes that already existing malnutrition predisposes to increased severity of malaria. Though, there are inconsistent results in studies carried out to observe whether already existing malnutrition can predispose to and increase severity of malaria. Interventional studies have shown that with control of malaria, malnutrition rate in children can be brought down effectively
      • Friedman J.F.
      • Phillips-Howard P.A.
      • Hawley W.A.
      • et al.
      Impact of permethrin-treated bed nets on growth, nutritional status, and body composition of primary school children in western Kenya.
      Many revolutionary steps have been taken since long to control malaria; still control of malaria is far from satisfactory. It's a cause of morbidity and mortality of large proportion of children and globally its sixth leading cause of death in children <5 years
      • Wang H.
      • Bhutta Z.A.
      • Coates M.M.
      • et al.
      Global, regional, national, and selected subnational levels of stillbirths, neonatal, infant, and under-5 mortality, 1980–2015: a systematic analysis for the Global Burden of Disease Study 2015.
      especially most vulnerable subpopulation of malnourished children. Hence effective nutritional intervention programme should be consolidated with malaria control programmes.
      Limitations of Study: In this study, children were selected conveniently from OPD/Ward of tertiary care hospital of a District from Uttar Pradesh, India. Hence, most of the children were residing in urban slums and belonging to lower socioeconomic class. Therefore, a detailed analysis of assosciation of severity of malaria with malnutrition in relation to sociodemographic.
      Variables could not be done. However, study gives insight of relation of malnutrition and severe malaria in different pediatric age groups.

      7. Conclusion

      Amongst 200 cases of severe malaria, we found higher percentage of children to be malnourished. We did not observe any species of malaria affecting malnourished children in 0.5 – 5years of age group significantly higher than other species. Other interesting observation was that in 5–18 years of age group, P.vivax and mixed malaria was significantly higher than P.falciparum. These results are very important as these indicate that underlying undernutrition in children can be a major obstacle in achieving ambitious goal of malaria elimination. As relationship between malaria and malnutrition is synergistic, nutritional intervention programmes should be integrated with malaria elimination programmes and vice-versa. Better understanding of complex associations between both will help guide much needed interventions to control malaria, curb malnutrition and also optimise antimalarial drug dosing in malnourished children. Further, studies should be done with larger sample size to study effect of P.vivax on nutritional status amongst different age group of children.

      Funding

      This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sector.

      Declaration of competing interest

      The authors declare no conflict of interest.

      Acknowledgement

      Authors acknowledge the immense help received from the scholars whose articles are cited and included in references of this manuscript. The authors are also grateful to authors/editors/publishers of all those articles, journals and books from where the literature for this article has been reviewed and discussed.

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