Hrev_master [Healthcare in Low-resource Settings 2017; 5:6401] [page 7] C-reactive protein as a marker of infection in children with severe acute malnutrition in Khartoum state, Sudan Abdelmoneim E.M. Kheir, Balla G. Gebreel Department of Paediatrics and Child Health, University of Khartoum and Soba University Hospital, Khartoum, Sudan Abstract Severe acute malnutrition and acute systemic infection are often synergistic in children and lead to considerable mortality. The main aim of this research was to deter- mine whether children with severe acute malnutrition can mount an acute phase reac- tant response measured by C-reactive pro- tein. This was a descriptive, cross-sectional, hospital-based study that was carried out in the five main children hospitals in Khartoum state, from November 1st, 2012 to March 1st, 2013. 132 children with severe acute malnutrition were included in the study. Data collection included history, examination and C-reactive protein meas- urement. The data were analyzed using Statistical Package for Social Sciences (SPSS) for descriptive and inferential statis- tics. The main results revealed that 93(70.5%) children between 12-23 months of age and most of them had marasmus. Diarrhoea was the commonest presenting symptoms in 86.4%, followed by fever and vomiting. Most of the children (82.6%) had positive C-reactive protein with variable levels. In conclusion malnourished children are able to synthesize C-reactive protein in response to an infectious process and the magnitude of this response is increased in those with severe infections. Introduction Malnutrition remains one of the most common causes of morbidity and mortality among children throughout the world. It is estimated that, in developing countries, more than one-quarter of all children younger than 5 years of age are malnour- ished.1 Malnutrition diminishes immune function and prevents the host from mount- ing an adequate protective response to infectious agents. In turn, infections alter nutrient status and can create a deficiency state. Thus, malnutrition and infection often act synergistically to increase morbidity and mortality, particularly among infants and children.2 Several studies on the effect of malnu- trition at the immunological level have been carried out with humans and experimental animals. These studies indicate that malnu- trition decreases T-cell function, cytokine production, and the ability of lymphocytes to respond appropriately to cytokines.3 The usual signs of infection are absent or nonspecific in children with acute severe malnutrition (SAM), Furthermore, laborato- ry diagnostic capacity is often limited in regions with the highest burdens of malnu- trition. Consequently, treatment is empiri- cal.4,5 Malnourished patients maintain the capacity to release inflammatory markers such as CRP & IL-6 which can be consid- ered favorable for combating infections.6 There are very few studies that have investigated the role of C reactive protein (CRP) as a diagnostic tool of infection in African children where infection profiles are different.7,8 This is further complicated by the fact that SAM, particularly edema- tous malnutrition, can be associated with reduced levels of acute phase proteins. 9 The main objectives of this study were to determine whether children with SAM can mount an acute phase reactant response namely CRP and to evaluate the usefulness of quantitative CRP as a predictor of severe infections in children with SAM. Materials and Methods This was a prospective, cross-sectional, hospital-based study that was carried out in the five main children hospitals in Khartoum state, during the period 1.11.2012 to 1.3 2013 (change this date for- mat). All children aged 6-59 months who were admitted with the diagnosis of SAM during their first three days of admission were included in the study. 132 children with SAM were recruited to participate in the study. The diagnosis of SAM was made using the recent WHO criteria measuring weight for length/height and mid-upper arm circumference (MUAC) and the presence of bilateral pitting oedema and severe wasting. Two forms of SAM exist in children: nonoedematous malnutrition, also known as marasmus, characterized by severe wasting and currently defined by weight for length/height z score < -3 of the WHO growth standard, or MUAC <11.5 cm; and oedematous malnutrition defined by bilater- al pitting oedema also known as Kwashiorkor.10 The term marasmic kwashi- orkor, has been used to describe children with both wasting and oedema.11 Children with malnutrition secondary to serious underlying conditions including congenital anomalies, inborn errors of metabolism, malignancies, inherited auto- somal disorders like cystic fibrosis, chronic diarrheal diseases like caeliac disease, con- genital cardiac diseases, chronic kidney dis- ease were excluded from the study. All children underwent detailed history and clinical examination by a senior mem- ber of the staff (registrar, consultant), per- sonal details were recorded like age, sex, residence, symptoms and signs of sepsis, bilateral pitting oedema and visible severe wasting. Anthropometric measurements were taken namely weight, length or height and MUAC. All those who were enrolled in this study, underwent blood sampling: (two mil- liliters of blood were drawn from a periph- eral vein under aseptic condition after cleaning the skin with 70% alcohol), then the serum was separated and sent for CRP measurement, using the latex agglutination test and patients were put into 5 groups according to CRP level:12,13 level less than 10 mg/L, regarded as normal; level from Healthcare in Low-resource Settings 2017; volume 5:6401 Correspondence: Abdelmoneim E.M. Kheir, Department of Paediatrics and Child Health, Faculty of Medicine, University of Khartoum and Soba University Hospital, P.O. Box 102, Khartoum, Sudan. Tel: +249 9 12313110 - Fax +249 183776295. E-mail: moneimkheir62@hotmail.com Acknowledgements: the authors express their sincere gratitude to the administrations of the five hospitals in Khartoum state for giving their permission to conduct this research. Thanks are also extended to the caregivers of the children who participated willingly. Key words: Malnutrition; Marasmus; Kwashiorkor C-reactive protein; Infection. Conflict of interest: the authors declare no potential conflict of interest. Contributions: the authors contributed equally, all authors read and approved the final manu- script. Funding: there was no research grant for this study. Received for publication: 21 November 2016. Accepted for publication: 2 February 2017. This work is licensed under a Creative Commons Attribution 4.0 License (by-nc 4.0). ©Copyright A.E.M. Kheir and B.G. Gebreel, 2017 Licensee PAGEPress, Italy Healthcare in Low-resource Settings 2017; 5:6401 doi:10.4081/hls.2017.6401 No n c om me rci al us e o nly [page 8] [Healthcare in Low-resource Settings 2017; 5:6401] 10-20 mg/L, regarded as elevated; level from 20-50 mg/L, may rule out serious bac- terial infections; level from 50-100 mg/L, suggests bacterial infections; level exceed- ing 100 mg/L, suggests serious bacterial infections. Other routine investigations were also done like stool analysis, urinalysis, random blood sugar, complete blood count, renal function test and electrolytes. CXR was done where applicable. Blood culture was done on few patients because it is not always available. The data was analyzed using the statistical package for social sci- ences (SPSS) version 20 for descriptive and inferential statistics. Chi-square test was used to test for significant association between SAM and the following independ- ent variables (age, sex, residence, MUAC, weight for height). Also, the association of CRP level and serious infections was stud- ied. P value of less than 0.05 was consid- ered significant. Ethical clearance and approval for con- ducting this research was obtained from the ethical committee of the Sudan medical specialization board. Prior informed con- sent was obtained from the caregivers of the individual subjects. Results A total of 132 children with SAM were included in this study. There were 76 (57.6%) males and 56 (42.4%) females, the male: female ratio was 1.36:1. The study revealed that 93(70.5%) children were 12- 23 months of age , 34(25.8%) between 24- 36 months and only 5(3.7%) between 36-59 months. Most of the children had marasmus and were lying between the age group 12- 23 months with significant association between age and type of SAM (P = 0.006) (Table 1). With regards to place of residence, 39(29.5%) were living in urban areas where as 93(70.5%) live in periurban areas with no significant association between place of res- idence and type of SAM (P= 0.072) (Table 2). 70 (53%) of the total participants had marasmus, 39 (29.5%) had kwashiorkor and 23 (17.4%) had marasmic-kwashiorkor. Regarding the presenting symptoms of the study population, 89 (67.4%) children had fever, 71(53.8%) had poor appetite, 114 (86.4%) had diarrhea, 83 (62.9%) had vom- iting, 100 (75.8%) had weight loss, 48 (36.4%) had cough, 4 (3.0%) had sore throat, 3 (2.3%) had ear discharge, 18 (13.6%) had skin lesions. 2 (1.5%) had burning micturition, 96 (72.7%) had pallor, 62 (47.0%) had oedema, and 3 (2.3%) had convulsions. Therefore diarrhea was the Article Table 1. Distribution of the study population according to age and type of severe acute malnutrition. Age in months Disease Total M MK K 12 up to 23 Count 41 18 34 93 % within Age 44.1 19.4 36.6 100.0 % within Disease 58.6 78.3 87.2 70.5 % of Total 31.1 13.6 25.8 70.5 24 up to 36 Count 27 3 4 34 % within Age 79.4 8.8 11.8 100.0 % within Disease 38.6 13.0 10.3 25.8 % of Total 20.5 2.3 3.0 25.8 36 up to 59 Count 2 2 1 5 % within Age 40.0 40.0 20.0 100.0 % within Disease 2.9 8.7 2.6 3.7 % of Total 1.5 1.5 .8 3.7 Total Count 70 23 39 132 % within Age 53.0 17.4 29.5 100.0 % within Disease 100.0 100.0 100.0 100.0 % of Total 53.0 17.4 29.5 100.0 M, Marasmus; K, Kwashiorkor; MK, Marasmic-Kwashiorkor. Table 2. Distribution of study population according to residence and type of severe acute malnutrition. Age in months Disease Total M MK K Residence Urban Count 20 11 8 39 % within residence 51.3 28.2 20.5 100.0 % within Disease 28.6 47.8 20.5 29.5 % of Total 15.2 8.3 6.1 29.5 Peri Urban Count 50 12 31 93 % within residence 53.8 12.9 33.3 100.0 % within Disease 71.4 52.2 79.5 70.5 % of Total 37.9 9.1 23.5 70.5 Total Count 70 23 39 132 % within residence 53.0 17.4 29.5 100.0 % within Disease 100.0 100.0 100.0 100.0 % of Total 53.0 17.4 29.5 100.0 M, Marasmus; K, Kwashiorkor; MK, Marasmic-Kwashiorkor. Table 3. Relation between mid-upper arm circumference and type of severe acute malnu- trition. MUAC Disease Total M MK K < 11.5 cm Count 44 11 28 83 % within MUAC 53.0 13.3 33.7 100.0 % within Disease 62.9 47.8 71.8 62.9 % of Total 33.3 8.3 21.2 62.9 11.5 - 12.5 cm Count 24 11 9 44 % within MUAC 54.5 25.0 20.5 100.0 % within Disease 34.3 47.8 23.1 33.3 % of Total 18.2 8.3 6.8 33.3 > 12.5 cm Count 2 1 2 5 % within MUAC 40.0 20.0 40.0 100.0 % within Disease 2.9 4.3 5.1 3.8 % of Total 1.5 .8 1.5 3.8 Total Count 70 23 39 132 % within MUAC 53.0 17.4 29.5 100.0 % within Disease 100.0 100.0 100.0 100.0 % of Total 53.0 17.4 29.5 100.0 MUAC, mid-upper arm circumference; M, Marasmus; K, Kwashiorkor; MK, Marasmic-Kwashiorkor. No n c om me rci al us e o nly [Healthcare in Low-resource Settings 2017; 5:6401] [page 9] most common presenting symptom (86.4%), while burning micturition was the least common (1.5%). The study showed that in 83 (62.9%) children MUAC was below 11.5 cm, out of these 44 (33.3%) had marasmus, 11(8.3%) marasmic-kwashiorkor and 28 (21.2%) had kwashiorkor, with no significant association between MUAC and type of SAM (P= 0.356) (Table 3). When considering weight for length/height, 86 cases (65.2%) had their weight for length/height less than -3SD, of whom 69 cases (52%) were marasmic, and 17 (12.9%) marasmic-kwashiorkor, and there was significant association between weight for length/height and SAM(P=0.00) (Table 4). All participants were subjected to quan- titative CRP measurement. 45 (34.1%) cases had CRP less than 10 mg/L, 32 (24.2%) cases had CRP level between 10- 20 mg/L, 22 (16.7%) cases had CRP level between 21-50 mg/L, 15 (11.4%) cases had CRP level between 51-100 mg/L and 18 cases (13.6%) had CRP level more than 100 mg/L, of whom 11 cases (8.3%) marasmus, 5 (3.8%) kwashiorkor and 2 (1.5%) maras- mic-kwashiorkor. The study revealed no significant association between CRP level and type of SAM (P=0.341) (Table 5). Out of these 18 cases with CRP more than 100mg/L, 3 (2.3%) cases had extensive infected skin lesions, 4 (3%)cases had pneu- monia based on X-ray. 4(3%) had gastroen- teritis, 2 (1.5%)cases had severe sepsis, both had blood cultures taken, in one sam- ple the result was contaminated and the par- ents refused a repeat sample. In the second sample klebsiella species was isolated. 1 case had urinary tract infection. 2 cases out of the 18 refused to continue after the result of CRP, while the remaining 2 discharged themselves against medical advice. There was significant association between CRP level and serious infections (Table 6) (P=0.000). Discussion Severe malnutrition and acute systemic infection are often synergistic in children.14 In the present study an attempt has been made to see whether children with SAM can mount an acute phase reactant response, namely CRP and to evaluate the usefulness of quantitative CRP as a predictor of severe infections in children with SAM. Our data indicated that most of the children (70.5%) were less than two years of age which is quite compatible with other reports from developing countries.15,16 Our study showed that diarrhoea was the commonest presenting symptoms in 86.4%, followed by fever and vomiting which is quite similar to the statistics of African and Asian countries though our fig- ure is slightly higher.17 It is stated that most children with severe protein–energy malnu- trition have asymptomatic infections because their immune system fails to respond with chemotaxis, opsonization and phagocytosis of bacteria, viruses or fungi, however this is not the finding in our study.18 Our data indicated that most of the chil- dren with SAM (82.6%) had positive CRP with variable levels and most of them were marasmus or marasmic-kwashiorkor, this Article Table 4. Relation between weight for height/length and type of severe acute malnutrition. Weight for height/length Disease Total M MK K - 1 to -2 SD Count 0 1 7 8 % within Wt.For.height 0.0 12.5 87.5 100.0 % within Disease 0.0 4.3 17.9 6.1 % of Total 0.0 0.8 5.3 6.1 -2 to -3 SD Count 1 5 32 38 % within Wt.For.height 2.6 13.2 84.2 100.0 % within Disease 1.4 21.7 82.1 28.8 % of Total 0.8 3.8 24.2 28.8 < - 3 SD Count 69 17 0 86 % within Wt.For.height 80.2 19.8 0.0 100.0 % within Disease 98.6 73.9 0.0 65.2 % of Total 52.3 12.9 0.0 65.2 Total Count 70 23 39 132 % within Wt.For.height 53.0 17.4 29.5 100.0 % within Disease 100.0 100.0 100.0 100.0 % of Total 53.0 17.4 29.5 100.0 SD, standard deviation; M, Marasmus; K, Kwashiorkor; MK, Marasmic-Kwashiorkor. Table 5. Relation of C-reactive protein with type of severe acute malnutrition. CRP Disease Total M MK K -< 10 mg/L Count 27 14 4 45 % within CRP 60.0 31.1 8.9 100.0 % within disease 38.6 35.9 17.4 34.1 % of total 20.5 10.6 3.0 34.1 10-20 mg/L Count 12 12 8 32 % within CRP 37.5 37.5 25.0 100.0 % within disease 17.1 30.8 34.8 24.2 % of total 9.1 9.1 6.1 24.2 20-50 mg/L Count 13 6 3 22 % within CRP 59.1 27.3 13.6 100.0 % within disease 18.6 15.4 13.0 16.7 % of total 9.8 4.5 2.3 16.7 50-100 mg/L Count 7 2 6 15 % within CRP 46.7 13.3 40.0 100.0 % within disease 10.0 5.1 26.1 11.4 % of total 5.3 1.5 4.5 11.4 > 100 mg/L Count 11 5 2 18 % within CRP 61.1 27.8 11.1 100.0 % within disease 15.7 12.8 8.7 13.6 % of total 8.3 3.8 1.5 13.6 Total Count 70 39 23 132 % within CRP 53.0 29.5 17.4 100.0 % within disease 100.0 100.0 100.0 100.0 % of total 53.0 29.5 17.4 100.0 P=0.135 CRP, C-reactive protein; M, Marasmus; K, Kwashiorkor; MK, Marasmic-Kwashiorkor. No n c om me rci al us e o nly [page 10] [Healthcare in Low-resource Settings 2017; 5:6401] indicates that children with SAM are able to synthesize CRP in response to infections and the magnitude is more (>100 mg/L) in those with severe infections, our finding is quite consistent with other similar studies which agreed that severely malnourished infected children are capable of increasing concentrations of CRP in response to infec- tious diseases.19,20 18 cases in our series had CRP level more than 100 mg/L, of whom 11 cases had marasmus. Amesty-Valbuena et al. reported a similar finding as they found high CRP levels in children with marasmus.20 The weaker response in the edematous group is not surprising and can be explained by the fact that Children with kwashiorkor, how- ever, differ from those with marasmus in having slower rates of whole-body protein breakdown, which may reduce the avail- ability of endogenous amino acids for CRP synthesis.19 It is interesting that there is one study which found that CRP levels in response to infection are lower in malnour- ished than in well-nourished children.21 Conclusions These results showed that malnourished children are able to synthesize CRP in response to an infectious process and the magnitude of this response is more in those with severe infections. High cost of other inflammatory markers precludes their clini- cal and routine application in low resource settings. Therefore, CRP being easily meas- urable and more affordable can be conve- niently used as a good marker for the diag- nosis of infection in children with SAM. References 1. United Nations Administrative Committee on Coordination. 2000. Fourth report on the world nutrition sit- uation. United Nations Administrative Committee on Coordination/Sub- Committee on Nutrition, Geneva, S w i t z e r l a n d . www.unscn.org/layout/modules/resourc es/files/rwns4.pdf 2. Calder PC, Jackson AA, Undernutrition, infection and immune function. Nutr Res Rev 2000;13:3-29. 3. Rodríguez L, González C, Flores L, et al. Assessment by flow cytometry of cytokine production in malnourished children. Clin Diagn Lab Immunol 2005;12:502-7. 4. Chisti MJ, Tebruegge M, La Vincente S, et al. Pneumonia in severely malnour- ished children in developing coun- tries—mortality risk, aetiology and validity of WHO clinical signs: a sys- tematic review. Trop Med Int Health 2009;14:1173-89. 5. Page AL, de Rekeneire N, Sayadi S, et al. Infections in children admitted with complicated severe acute malnutrition in Niger. PLoS ONE 2013;8:e68699. 6. Delgado AF, Okay TS, Leone C, et al. Hospital malnutrition and inflammatory response in critically ill children and adolescents admitted to a tertiary inten- sive care unit. Clinics (Sao Paulo) Article Table 6. Relation of C-reactive protein matching the level of serious infections with diagnosis. Based on Total None Clinical Chest Stool Blood diagnosis X-ray analysis & culture culture Urinalysis Infected skin lesions Count 0 3 0 0 0 0 3 % within Diagnosis 0.0 100.0 0.0 0.0 0.0 0.0 100.0 % within Bass on 0.0 100.0 0.0 0.0 0.0 0.0 16.7 % of Total 0.0 16.7 0.0 0.0 0.0 0.0 16.7 Pneumonia Count 0 0 4 0 0 0 4 % within Diagnosis 0.0 0.0 100.0 0.0 0.0 0.0 100.0 % within Bass on 0.0 0.0 100.0 0.0 0.0 0.0 22.2 % of Total 0.0 0.0 22.2 0.0 0.0 0.0 22.2 Gastroenteritis Count 0 0 0 4 0 0 4 % within Diagnosis 0.0 0.0 0.0 100.0 0.0 0.0 100.0 % within Bass on 0.0 0.0 0.0 100.0 0.0 0.0 22.2 % of Total 0.0 0.0 0.0 22.2 0.0 0.0 22.2 Sepsis Count 0 0 0 0 2 0 2 % within Diagnosis 0.0 0.0 0.0 0.0 100.0 0.0 100.0 % within Bass on 0.0 0.0 0.0 0.0 100.0 0.0 11.1 % of Total 0.0 0.0 0.0 0.0 11.1 0.0 11.1 U.T.I Count 0 0 0 0 0 1 1 % within Diagnosis 0.0 0.0 0.0 0.0 0.0 100.0 100.0 % within Bass on 0.0 0.0 0.0 0.0 0.0 100.0 5.6 % of Total 0.0 0.0 0.0 0.0 0.0 5.6 5.6 DAMA Count 2 0 0 0 0 0 2 % within Diagnosis 100.0 0.0 0.0 0.0 0.0 0.0 100.0 % within Bass on 50.0 0.0 0.0 0.0 0.0 0.0 11.1 % of Total 11.1 0.0 0.0 0.0 0.0 0.0 11.1 Refused to continue Count 2 0 0 0 0 0 2 % within Diagnosis 100.0 0.0 0.0 0.0 0.0 0.0 100.0 % within Bass on 50.0 0.0 0.0 0.0 0.0 0.0 11.1 % of Total 11.1 0.0 0.0 0.0 0.0 0.0 11.1 Total Count 4 3 4 4 2 1 18 % within Diagnosis 22.2 16.7 22.2 22.2 11.1 5.6 100.0 % within Bass on 100.0 100.0 100.0 100.0 100.0 100.0 100.0 % of Total 22.2 16.7 22.2 22.2 11.1 5.6 100.0 UTI, urinary tract infection; DAMA, discharged against medical advice. 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