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Keywords:

  • noma;
  • growth retardation;
  • malnutrition;
  • infections;
  • cytokines;
  • oro-facial gangrene

Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Ethical considerations
  6. Site of study
  7. Subjects
  8. Anthropometry
  9. Biochemical studies
  10. Interleukin-18 assay
  11. Statistical analysis
  12. Results
  13. Anthropometry
  14. Serum interleukin-18
  15. Discussion
  16. Acknowledgements
  17. References

Background  Fresh noma (cancrum oris) occurs predominantly in children <4 years of age. The key risk factors are poverty, malnutrition and infections. Evolution from an intraoral inflammation to a grotesque oro-facial gangrene is very rapid.

Objective  We assessed potential relationship between the occurrence of fresh noma and linear growth retardation (LGR) which is prevalent in deprived Third World infants/children between ages 3 and 30 months. LGR is attributed to malnutrition and chronic immunostimulation by environmental antigens.

Design  Anthropometric evaluation of children (n = 91) with fresh noma, ages 0–8 years, in relation to US National Center for Health Statistics Reference values was carried out. Age-matched noma-free, poor village children (n = 151) from similar communities as noma cases, and elite urban children (n = 132) served as control groups. Heights and weights were measured and the height for age (HAZ), weight for age (WAZ) and weight for height (WHZ) scores calculated as indices of stunting, underweight and wasting respectively. Serum level of interleukin (IL)-18, a multifunctional cytokine, was also measured.

Results  In the age groups 0–4 and 4–8 years, the percentages of noma children <−2.0SD were 91% and 67% respectively. The corresponding values for the village children were 37% and 24% and significantly different (P < 0.001) from the noma group. Only 7% of the elite children aged 4–8 years were stunted. Low body weight and wasting were prominent features of village and noma groups, but more marked in the latter. Associated with noma was a profound increase (P < 0.001) in IL-18 in comparison with urban controls, and a 34% non-statistically significant increase relative to the village control group. Among other functions, IL-18 induces several pro-inflammatory cytokines and the matrix metalloproteinases, influences long bone growth, and consequently may be relevant to growth retardation seen in poor village children and noma victims.

Conclusion  These results suggest that occurrence of fresh noma was probably programmed very early in life by malnutrition and chronic infections resulting from replacement of breast milk with contaminated, inferior substitutes. Although not investigated, we speculate that children with fresh noma might also be victims of intrauterine growth retardation as noma is most prevalent during the infantile phase of child growth which starts at mid-gestation and tails off at 4 years.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Ethical considerations
  6. Site of study
  7. Subjects
  8. Anthropometry
  9. Biochemical studies
  10. Interleukin-18 assay
  11. Statistical analysis
  12. Results
  13. Anthropometry
  14. Serum interleukin-18
  15. Discussion
  16. Acknowledgements
  17. References

Noma (cancrum oris), a debilitating oro-facial gangrene, starts as a localized gingival ulceration and spreads rapidly through the oro-facial tissues, establishing itself with a well-demarcated perimeter surrounding a blackened necrotic centre (Tempest 1966; Enwonwu et al. 2000). The lesion may spread through anatomical barriers such as muscles, contrary to infectious processes of the face, which usually expand along cellular spaces of the head and neck (Evrard et al. 1996). Fresh cases of noma are seen predominantly in the 1–4 years age group, although late stages of the disease occur in adolescents and adults (Tempest 1966; Enwonwu 1972; Barmes et al. 1997). The World Health Organization designates noma a health priority (Bourgeois & Leclercq 1999), and has suggested a global incidence of 140 000 cases with prevalence in 1997 of 770 000 victims (Bourgeois et al. 1999). A recent report estimates an annual incidence of 6.4 per 1000 children in north-west Nigeria, and by extrapolation, an incidence of 25 000 for the developing countries bordering the Sahara desert (Fieger et al. 2003).

The aetiology of noma is poorly understood. Poverty is the key risk condition for development of noma (Enwonwu 1995; Obiechina et al. 2002), a disease appropriately described as the ‘face of poverty’ in the developing world (Marck 2003). The environment in which noma thrives is characterized by severe malnutrition, unsafe drinking water, deplorable sanitary practices, limited or no access to quality healthcare services, residential proximity to unkempt animals, and a high prevalence of diseases such as measles, malaria, diarrhoea, pneumonia and tuberculosis (Enwonwu et al. 1999; Falkler et al. 1999a; Idigbe et al. 1999). Acute necrotizing gingivitis has for many years been assumed to be the essential precursor of noma (Enwonwu 1972; Baratti-Mayer et al. 2003), but this view is now disputed (Enwonwu 1995; Adedoja et al. 2002).

Growth assessment is the single measurement that best defines the status of health and nutrition in infants and children (de Onis et al. 1993). In deprived communities in the developing world, growth faltering in infants occurs in association with introduction of weaning foods at about 3–4 months of age and continues until about 3 years of age (Lunn 2002; de Onis & Blosner 2003). Linear growth retardation (LGR) or stunting in children is usually associated with impaired integrity of gut epithelium and is attributed to malnutrition and a continuous burden of chronic immunostimulation by environmental antigens (Solomons et al. 1993; Campbell et al. 2003). In view of the overlap between the timing of LGR in children and the peak age incidence of acute, fresh noma in the communities, it was our hypothesis that the genesis of the latter was interwoven with the former. We therefore evaluated anthropometric parameters in noma children in the anticipation that an indicator like height/length for age, which should not change rapidly with illness (Rice et al. 2000), would provide useful clues regarding the health and nutrition status of the children prior to clinical manifestation of the lesion. For comparative purposes, age-matched children without noma were included in the study. As bone growth is affected by inflammatory mediators (Stephensen 1999), we also measured serum levels of interleukin (IL)-18, a pleiotropic participant in chronic inflammation, which has both pro- and anti-inflammatory actions, and degrades cartilage by reducing chondrocyte proliferation as well as activating matrix metalloproteinases (Okamura et al. 1998; Kashiwamura et al. 2002).

Ethical considerations

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Ethical considerations
  6. Site of study
  7. Subjects
  8. Anthropometry
  9. Biochemical studies
  10. Interleukin-18 assay
  11. Statistical analysis
  12. Results
  13. Anthropometry
  14. Serum interleukin-18
  15. Discussion
  16. Acknowledgements
  17. References

This project was carried out with the prior approval of the Institutional Review Board (IRB) of the University of Maryland School of Medicine, the Ministry of Health in Sokoto State, Nigeria, and all the relevant State Ministries of Education and Hospital Management Boards where study subjects were recruited. The project was classified as high risk by the IRB because of the severe state of debilitation of malnourished children afflicted with acute noma. Village chiefs in charge of the relevant rural communities also gave their consent to the study. Informed consent was obtained from the children's parents or legal guardians, often in the presence of a neutral primary healthcare worker, and in all cases, the child's dissent prevailed over parental permission.

Site of study

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Ethical considerations
  6. Site of study
  7. Subjects
  8. Anthropometry
  9. Biochemical studies
  10. Interleukin-18 assay
  11. Statistical analysis
  12. Results
  13. Anthropometry
  14. Serum interleukin-18
  15. Discussion
  16. Acknowledgements
  17. References

A major site of the study was the Noma Children Hospital, a 60-bed hospital established in 1999 in Sokoto State, North-Western Nigeria. Prior to 1999, the Sokoto Specialist Hospital served as a study site. An average of 55–75 new cases of noma were seen annually in these facilities. Details about the demography of Sokoto State have been reported (Enwonwu et al. 1999). Indigenes of the rural communities resided in over-crowded poorly ventilated huts with dirt floors and usually in very close proximity to their domestic animals (Idigbe et al. 1999). Drinking water was obtained mainly from contaminated shallow wells, and facilities for safe disposal of human and animal faecal wastes were grossly inadequate.

The principal health problems in the communities were infections such as malaria, measles, tuberculosis, pneumonia, diarrhoea and malnutrition (Idigbe et al. 1999). Prevalence of low birthweight in such rural northern Nigerian villages is above 20% (Rehan & Tafida 1981), and it is attributable mainly to intrauterine growth retardation (Ransome-Kuti 1985). The infant mortality rate was estimated to be 114/1000 live births, and mortality among children <5 years is as high as 300/1000 live births in some communities. Exclusive breastfeeding in the first 3 months of life is extremely rare in Nigerian villages, and the reported prevalence varies from <2% (Davies-Adetugbo 1996) to about 12.1% (Adelekan 2003). Supplementary foods given to infants included locally obtained cows’ milk, glucose water, herbal tea and various indigenous cereal-based diets. Immunization coverage against measles and other childhood diseases is usually extremely low.

Subjects

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Ethical considerations
  6. Site of study
  7. Subjects
  8. Anthropometry
  9. Biochemical studies
  10. Interleukin-18 assay
  11. Statistical analysis
  12. Results
  13. Anthropometry
  14. Serum interleukin-18
  15. Discussion
  16. Acknowledgements
  17. References

This investigation was a combination of case–control and cross-sectional study. Over a period of 4 years (1997–2001), children with noma presenting at the Noma Hospital were screened. A few days prior to the arrival of the research team from Baltimore, MD, USA, our collaborating local group urged all parents whose infants/children had oral infections to bring these sick children to the hospital/clinic. Contact with the remote rural villages was usually through radio messages. Additionally, our field team, which included physicians, dentists, and other health personnel actively sought for noma cases through house/hut visits in various local government areas. Only fresh incident noma cases were recruited into this study. Diagnosis of noma was as previously reported (Enwonwu 1972; Falkler et al. 1999a). Exclusion criteria included prevalent cases of noma, congenital abnormalities, concurrent presence of other overt infectious diseases, clinical evidence of potential HIV-infection/AIDS as judged by presence of oral pseudomembranous candidiasis, and subsequent serological evidence of HIV-infection. Restricting the study to incident cases with exclusion of prevalent cases was a selection bias which seriously limited the number studied. Two age-matched control groups were randomly recruited into the study during the same time period as the noma children. The first control group, referred to as the ‘Village Control’ included children without noma or other overt infections, and were from the same socioeconomically deprived, malnourished rural communities as the children with noma. The second control group (urban control) included Nigerian children of the educated, professional elite families resident in relatively affluent sections of the cities. The control groups were children attending the primary healthcare centres for routine immunizations. In selecting the village neighbourhood children as one set of the controls, it was our anticipation that if the occurrence of noma was associated with prolonged growth retardation, particularly stunting, the prevalence and severity of the latter should be greater in noma victims than in their neighbourhood counterparts without noma. Our decision to include an extra control group drawn from elite, urban children was predicated on the fact that the neighbourhood control children would not accurately represent the rate of growth expected in a population of non-diseased individuals (Enwonwu et al. 1999). Additionally, noma had never been reported in infants/children of elite Nigerians residing in urban areas (Enwonwu 1972; Enwonwu et al. 2000).

To increase the power of the study, our original plan was to study two controls each of neighbourhood children and urban elites per case of noma. This was not possible for various reasons, particularly lack of accurate determination of age, and presence of other health conditions likely to affect growth.

Anthropometry

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Ethical considerations
  6. Site of study
  7. Subjects
  8. Anthropometry
  9. Biochemical studies
  10. Interleukin-18 assay
  11. Statistical analysis
  12. Results
  13. Anthropometry
  14. Serum interleukin-18
  15. Discussion
  16. Acknowledgements
  17. References

Body weight was measured to the nearest 50 g. Children <3 years of age were weighed using a balance beam scale, and those older than 3 years on a standing beam scale. Length/height was measured to the nearest 0.1 cm. For children under 3 years of age, height was measured as supine length, and for those older than 3 years, standing height was determined using a stadiometer attached to a wall. Assessment of nutrition and health status was carried out using low weight for height, low height for age and low weight for age as indices of wasting, failure to grow/stunting, and body mass relative to chronological age respectively (de Onis 2001; Fernandez et al. 2002). In most cases, wasting is a reflection of a recent and severe process of weight loss often resulting from a severe disease and/or acute starvation, whilst low height for age in children 2–3 years of age is an indication of a continuing process of growth failure (de Onis 2001). Height for age (HAZ), weight for height (WHZ) and weight for age (WAZ) Z-scores [standard deviation (SD) scores] were calculated using the EPI 2000 program from the Centers for Disease Control and Prevention, Atlanta, GA, USA. This software program uses the National Center for Health Statistics (NCHS 1977) references values. In this study, we chose the Z-score cut-off points of −2SD, −3SD and −4SD of the reference median to reflect moderate, severe and critical malnutrition/poor health status respectively.

Age was determined from birth records where available, and more importantly, from interviews with mothers/legal guardians, using a validated local calendar of important ceremonial/cultural events occurring in recent months/years as a guide. Usually, the local calendar was constructed after a focus group discussion with parents in the communities. In a few instances, the reported timing of dental eruption in Nigerian children was used as an additional guide (Enwonwu 1973). Children whose ages could not be ascertained with any reasonable degree of certainty were treated for their health problems, and excluded from the study.

Biochemical studies

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Ethical considerations
  6. Site of study
  7. Subjects
  8. Anthropometry
  9. Biochemical studies
  10. Interleukin-18 assay
  11. Statistical analysis
  12. Results
  13. Anthropometry
  14. Serum interleukin-18
  15. Discussion
  16. Acknowledgements
  17. References

As part of a much larger study of circulating inflammatory mediators in malnourished Nigerian children, venous blood was collected into plain and heparinized tubes from randomly selected subjects between 8:00 and 10:00 am. Because of the high-risk nature of the study, no more than 5 ml of blood was collected from each child, and only at one encounter. Care was taken to protect the blood samples from undue exposure to light, heat and air. The blood samples in tubes were centrifuged (2000 g for 10 min), usually within 30 min after collection. The separated plasma and serum were divided into aliquots for storage at −70 °C and subsequent analysis. Haemolyzed samples were excluded from the study and many of such samples were from children with noma. The cytokine assay was carried out within 1–3 months of blood collection.

Interleukin-18 assay

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Ethical considerations
  6. Site of study
  7. Subjects
  8. Anthropometry
  9. Biochemical studies
  10. Interleukin-18 assay
  11. Statistical analysis
  12. Results
  13. Anthropometry
  14. Serum interleukin-18
  15. Discussion
  16. Acknowledgements
  17. References

Enzyme-linked immunosorbent assay for IL-18 was performed according to the instructions from the manufacturer of the kits (Biosource International, Inc., Camarillo, CA, USA). Plates were read at 450 nm using Packard SpectracountTM plate reader and i smart 2.0 software. The minimum detectable concentration of IL-18 was 12.5 pg/ml.

Statistical analysis

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Ethical considerations
  6. Site of study
  7. Subjects
  8. Anthropometry
  9. Biochemical studies
  10. Interleukin-18 assay
  11. Statistical analysis
  12. Results
  13. Anthropometry
  14. Serum interleukin-18
  15. Discussion
  16. Acknowledgements
  17. References

The data are expressed as mean ± SD or as median, unless indicated otherwise. Statistical analyses were carried out using SPSS 11.5 for windows (SPSS Inc., Chicago, IL, USA). Differences were considered statistically significant when P < 0.05.

The age distribution of children in each study group was not normal. Therefore, comparisons of the ages between groups were carried out using non-parametric Kruskal–Wallis test and the Dunn's multiple comparison test.

For the anthropometric data, calculated Z scores in each group were tested for normality by Kolmogorov and Smirnov test and then their mean values were compared using a one-way anova and Tukey–Kramer multiple comparison test.

The Z scores for each group were then classified as Z ≤ −2, −3 and −4SD and the numbers of Z scores in each subgroup transformed into a percentage of the total. Comparisons of percentages between the groups were made by Fisher's exact test using GraphPad InStat version 3.00 for Windows 95 (GraphPad Software, San Diego CA, USA: http://www.graphpad.com). Comparison of IL-18 levels between the groups was by analysis of variance (anova), with Tukey–Kramer multiple comparison test, following logarithmic transformation of the values.

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Ethical considerations
  6. Site of study
  7. Subjects
  8. Anthropometry
  9. Biochemical studies
  10. Interleukin-18 assay
  11. Statistical analysis
  12. Results
  13. Anthropometry
  14. Serum interleukin-18
  15. Discussion
  16. Acknowledgements
  17. References

Figure 1 typifies a case of fresh noma as seen in an impoverished rural Nigerian community. According to the girl's guardian, the child had a fever, presumably measles, a few weeks prior to development of an oral ulcer which evolved very rapidly, perforating the swollen cheek in a matter of days. The fairly localized gangrene had a yellowish groove surrounding a blackened necrotic centre (Figure 1). Intra-oral examination revealed extensive necrosis involving right posterior quadrants of both the maxilla and mandible. At age 2 years, this child had a length of 70 cm and a body weight of 6.0 kg, which were 82% and 50% respectively of the reference standards. The HAZ, WAZ and WHZ scores for this child were −4.52, −4.94 and −2.61 respectively, which were indicative of long-term as well as continuing severe malnutrition and poor health.

image

Figure 1. Picture of a 2-year-old Nigerian child with fresh noma. At the time of evaluation, the child weighed 6 kg and was 70 cm in length. These yielded Z-scores of −4.52, −4.94 and −2.61 for HAZ, WAZ, and WHZ respectively. History from the mother suggested measles infection a few weeks prior to the development of oro-facial lesion.

Download figure to PowerPoint

Anthropometry

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Ethical considerations
  6. Site of study
  7. Subjects
  8. Anthropometry
  9. Biochemical studies
  10. Interleukin-18 assay
  11. Statistical analysis
  12. Results
  13. Anthropometry
  14. Serum interleukin-18
  15. Discussion
  16. Acknowledgements
  17. References

For analysis of the anthropometric data, each study group was divided into two non-overlapping age groups (0–4 years; >4 to 8 years.). Table 1 summarizes the findings in children 0–4 years of age. Mean HAZ and WAZ scores were significantly, different (P < 0.001) between the three experimental groups, and were the poorest in the children with noma. While no urban, elite child was stunted, underweight, or wasted as judged by the percentage below the National Centre for Health Statistics median minus 2SD, the prevalence of stunting varied from 37% in the village group to 91% in the noma group (Table 1). Seventy per cent of the noma children in this age range were severely stunted, while 43% were critically stunted. Comparative values for the village children were 13% and 8% and significantly different (P < 0.001) from the noma group. Similarly, most of the victims of noma were severely underweight in comparison with their village counterparts without the disease. Findings in Table 1 also show that many village and noma children were wasted, with the severity more prominent in the noma patients. There were improvements in the anthropometric parameters in the older children (>4 to 8 years) (Table 2) compared with younger ones (0–4 years), but the prevalence and severity of stunting, underweight, and wasting were still prominent.

Table 1.  Anthropometric data for children 0–4 years
ItemUrban control (n = 26)Village control (n = 55)Noma group (n = 58)
  1. Values with the same superscript are significantly different between groups (aP < 0.001; bP < 0.05; cP < 0.005).

Age, years (mean ± 1SD)2.45 ± 1.082.40 ± 1.282.58 ± 1.02
 Median2.02.03.0
 Range1.0–4.00.3–4.00.1–4.0
HAZ (mean ± 1SD)1.06 ± 1.6a−1.43 ± 2.22a−3.82 ± 2.16a
 Median0.85−1.41−3.74
 Range−1.1–3.9−5.6–7.4−7.7–5.2
 %<−2.0SD37a91a
 %<−3.0SD13a70a
 %<−4.0SD8a43a
WAZ (mean ± 1SD)0.89 ± 1.47a−1.87 ± 1.67a−3.65 ± 1.82a
 Median0.62−1.88−3.54
 Range−1.2–4.9−5.6–2.3−6.7–3.0
 %<−2.0SD47a88a
 %<−3.0SD21c81c
 %<−4.0SD10b47b
WHZ (mean ± 1SD)0.44 ± 1.4a,b−1.14 ± 1.74b−1.97 ± 2.09a
 Median0.52−1.08−1.82
 Range−1.6–3.5−6.1–2.6−7.4–4.0
 %<−2.0SD32a44a
 %<−3.0SD8a24a
 %<−4.0SD5b15b
Table 2.  Anthropometric data for children >4 to 8 years
ItemUrban control (n = 106)Village control (n = 96)Noma group (n = 33)
  1. Values with the same superscript are significantly different between groups (aP < 0.001; bP < 0.05; cP < 0.005).

Age, years (mean ± 1SD)6.65 ± 1.14a5.92 ± 1.02a6.26 ± 1.03
 Median7.06.06.0
 Range5.0–8.04.3–8.04.5–8.0
HAZ (mean ± 1SD)0.22 ± 1.40a−0.96 ± 1.36a−2.64 ± 2.94a
 Median0.28−1.2−3.25
 Range−3.7–3.7−3.2–1.9−6.4–4.9
 %<−2.0SD7a24a67a
 %<−3.0SD3755
 %<−4.0SD33
WAZ (mean ± 1SD)−0.29 ± 1.15a−1.49 ± 1.11a−2.87 ± 1.65a
 Median−0.29−1.52−3.02
 Range−3.7–3.3−5.0–0.3−6.2–1.3
 %<−2.0SD8a37a76a
 %<−3.0SD1a3a52a
 %<−4.0SD2a18a
WHZ (mean ± 1SD)−0.68 ± 0.96a,b−1.27 ± 1.32b−1.98 ± 2.14a,b
 Median−0.72−1.19−1.34
 Range−2.9–2.6−5.6–1.9−8.5–1.1
 %<−2.0SD8a25a36a
 %<−3.0SD7c30c
 %<−4.0SD3b15b

Serum interleukin-18

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Ethical considerations
  6. Site of study
  7. Subjects
  8. Anthropometry
  9. Biochemical studies
  10. Interleukin-18 assay
  11. Statistical analysis
  12. Results
  13. Anthropometry
  14. Serum interleukin-18
  15. Discussion
  16. Acknowledgements
  17. References

Serum IL-18 levels observed in the children are summarized in Table 3. Despite marked individual variability within each group, the noma group showed a threefold, significant (P < 0.001) increase in IL-18 concentration compared with the urban control group. The mean value of IL-18 was 35% higher in noma children compared with the village control but the difference was not statistically significant.

Table 3.  Serum levels of Interleukin-18
GroupMean ± SD (pg/ml) [95% CI]Median (pg/ml)
  1. CI, confidence interval; mean values with the same superscript significantly different (P < 0.001) from each other.

Urban control (n = 45)459.0 ± 291.1a,b [371.5–546.5]402.1
Village control (n = 28)1096.3 ± 416.5b [934.8–1257.8]1082.4
Noma (n = 26)1482 ± 1034.2a [1064.3–1899.9]1119.2

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Ethical considerations
  6. Site of study
  7. Subjects
  8. Anthropometry
  9. Biochemical studies
  10. Interleukin-18 assay
  11. Statistical analysis
  12. Results
  13. Anthropometry
  14. Serum interleukin-18
  15. Discussion
  16. Acknowledgements
  17. References

The two periods of highest vulnerability to growth failure in the human are during intrauterine development and the transition from exclusive reliance on breast milk to weaning diets. In fact, almost all of the growth retardation reported in studies carried out in developing countries has its origin in the first 2 or 3 years of life (de Onis 2001). The level of stunting noted in rural communities studied, described here as village control, was 37% in the 0–4 years age group (Table 1), an observation consistent with reports in similar age groups in other African communities (de Onis et al. 1993; de Onis 2001; Campbell et al. 2002) where malnutrition and poor health are prevalent. Adelekan (2003) in an earlier report noted that stunting in Nigerian children commences early in life and increases with age, ranging from 25% in infants 6–11 months to 53% in children 48–59 months. The same study reports prevalence in north-west Nigerian children to be 50.4%. Our studies demonstrated quite clearly that fresh cases of noma seen in Nigeria were profoundly growth retarded (Tables 1 and 2). In the age group 0–4 years, virtually all the children with noma studied were markedly stunted and underweight with more than a third of them critically affected (<−4.0SD) (Table 1). Stunting in children is a cumulative process that can start in utero (Rice et al. 2000). Regretably, most of the children in poor Nigerian rural communities, including the noma children, were born at home often under the care of traditional birth attendants who kept no records of birth weights. It is however known that the prevalence of low birthweight is as high as 20% in Northern Nigerian rural communities, similar to the catchment area of the noma cases studied (Rehan & Tafida 1981; Ransome-Kuti 1985). The extent if any, to which low birthweight contributed to the profoundly impaired growth velocity in the noma infants and children, could not be assessed from this study.

Growth faltering, particularly retarded linear growth, which is common in infants in developing countries, becomes noticeable at about 3–4 months postnatally with the introduction of contaminated, indigenous weaning foods to an immature infant, and is substantially complete at about 20–36 months (Allen 1994; Filteau 2000; Thurnham et al. 2000). Malnutrition is believed to account for no more than 40% of the variance in the occurrence of LGR which is attributed mainly to the continuous burden of immunostimulation by environmental antigens (Lunn et al. 1991; Solomons et al. 1993). Solomons (2003) likens stunting in a developing country child to impaired growth of poultry and livestock reared under unsanitary conditions. In some earlier publications, we had reported on the very poor nutritional status/dietary habits of the Nigerian communities at high risk for noma (Enwonwu et al. 1999), and the deplorable environmental settings in which they live (Idigbe et al. 1999). Exclusive breastfeeding in Nigerian rural communities has a very low prevalence estimated at below 12% in the first 3 months of life (Davies-Adetugbo 1996; Nwankwo & Brieger 2002), and our random interviews as part of on-going nutritional studies in rural communities in north-west Nigeria, including Sokoto state, confirmed such low estimates (C.O. Enwonwu et al., unpublished findings). Equally ominous was the information gathered from some of the women to the effect that many of them feed their infants with raw milk obtained directly from the cows. This can damage the gut mucosa (Filteau 2000). Evidence of severe deficiencies of vitamin A and zinc had earlier been reported in the Sokoto rural communities, particularly in the victims of noma (Enwonwu et al. 1999). Such nutrient deficiencies do promote impaired integrity of the gastrointestinal tract mucosa. Several studies in Gambian children by Lunn and his team have underscored the close association between stunting and chronic inflammatory enteropathy of the small intestinal mucosa (Lunn 2002; Campbell et al. 2003). They have also demonstrated that small bowel enteropathy in the children is prominent at age 2 years, but improves with age along with improvement in WAZ and HAZ scores as well as the nutritional status (Campbell et al. 2002).

Our studies showed prominently increased serum level of IL-18 in noma victims and in the village children at risk for the disease in comparison with the relatively affluent urban children (Table 3). The results of on-going studies in our laboratory also suggest marked increases in circulating levels of several other pro-inflammatory cytokines in the village and noma children (C.O. Enwonwu, unpublished findings). Other investigators have also reported significantly increased plasma levels of IL-6 and the soluble receptors of tumour necrosis factor (TNF) α in malnourished African children (Sauerwein et al. 1997). Longitudinal bone growth is the result of chondrocyte proliferation and subsequent endochondral ossification in the epiphyseal growth plate (Price et al. 1994), and it is known that increased proinflammatory cytokines do impair bone remodelling required for long bone growth (Stephensen 1999). This could offer an explanation for the growth retardation noted in the village and noma children (Tables 1 and 2). Similar to our findings (Table 3), increased circulating IL-18 levels have been reported in several growth-retarding human conditions such as sepsis (Oberholzer et al. 1998), measles (Okada et al. 2001), falciparum malaria (Nagamine et al. 2003), and Crohn's disease (Monteleone et al. 1999). IL-18 has a widespread expression in many cell types including immune and non-immune cells (Dinarello 1999). It is a multifunctional cytokine involved in reduction of chondrocyte proliferation, inhibition of formation of osteoclasts, induction of several cytokines (e.g. TNF-α, IL-1β, IL-8, IL-4, etc.), activation of matrix metalloproteinases and abrogation of oral tolerance among other activities (Akira 2000; Eaton et al. 2003).

Studies in malnourished Nigerian children at risk for noma as well as in noma children have revealed very prominent recovery of anaerobic micro-organisms usually associated with severe periodontitis in adults (Falkler et al. 1999a,b). Epithelial cells, including oral mucosal cells in contact with microbes, secrete many inflammatory mediators such as IL-8 to alert various cell types and also attract neutrophils (Darveau et al. 1997; Sandros et al. 2000). IL-18 is constitutively expressed by oral epithelial cells and is activated by neutrophil proteinase 3 (Sugawara et al. 2001), thus suggesting a possible role for this cytokine in oral mucosal inflammation (Brandtzaeg 2001; Rouabhia et al. 2002). Although the 35% difference between the mean circulating levels of IL-18 in the village and noma children was not statistically significant (Table 3), it may have some clinical importance and this is the subject of further studies.

The health threat of emerging noma in Sub-Saharan African countries is caused by malnutrition and a severe breakdown in public health measures. Most children in the impoverished rural communities reside in conditions ripe for occurrence of noma. Although only relatively few cases are reported annually (Fieger et al. 2003), it is believed that many more victims of the disease die unseen for various reasons (Barmes et al. 1997). Findings in the present study indicate that prevention of noma would benefit not only from poverty eradication, improved nutrition particularly emphasizing appropriate breastfeeding practices, adequate sanitation, but most importantly, from increased awareness of the nutrition and health needs of women to ensure optimal growth of the developing foetus and promote adequate lactation.

Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Ethical considerations
  6. Site of study
  7. Subjects
  8. Anthropometry
  9. Biochemical studies
  10. Interleukin-18 assay
  11. Statistical analysis
  12. Results
  13. Anthropometry
  14. Serum interleukin-18
  15. Discussion
  16. Acknowledgements
  17. References

USPHS Grant DE43TW00907A from the US National Institutes of Health (Forgarty International Center) and a grant from Nestle Foundation, Lausanne, Switzerland supported this project. The excellent secretarial assistance of Ms. Yulvonnda Brown is also acknowledged.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Ethical considerations
  6. Site of study
  7. Subjects
  8. Anthropometry
  9. Biochemical studies
  10. Interleukin-18 assay
  11. Statistical analysis
  12. Results
  13. Anthropometry
  14. Serum interleukin-18
  15. Discussion
  16. Acknowledgements
  17. References
  • Adedoja D, Kabue MM & Sahila P (2002) Cancrum oris in HIV infected children in Lesotho: report of two cases. East African Medical Journal 79, 499501.
  • Adelekan DA (2003) Childhood nutrition and malnutrition in Nigeria. Nutrition 19, 179181.
  • Akira S (2000) The role of IL-18 in innate immunity. Current Opinion in Immunology 12, 5963.
  • Allen LH (1994) Nutritional influences on linear growth: a general review. European Journal of Clinical Nutrition 48 (Suppl. 1), S75S89.
  • Baratti-Mayer D, Pittet B, Montandon D et al. (2003) Noma: an ‘infectious’ disease of unknown aetiology. The Lancet Infectious Diseases 3, 419431.
  • Barmes DE, Enwonwu CO, Leclercq M-H, Bourgeois D & Falkler WA (1997) Editorial: the need for action against oro-facial gangrene (noma). Tropical Medicine and International Health 2, 11111114.
  • Bourgeois DM & Leclercq MH (1999) The World Health Organization initiative on noma. Oral Diseases 5, 172174.
  • Bourgeois DM, Diallo B, Frieh C & Leclercq MH (1999) Epidemiology of the incidence of oro-facial noma: a study of cases in Dakar, Senegal 1981–1993. American Journal of Tropical Medicine and Hygiene 61, 909913.
  • Brandtzaeg P (2001) Inflammatory bowel disease: clinics and pathology. Do inflammatory bowel disease and periodontal disease have similar immunopathogenesis? Acta Odontologica Scandinavica 59, 235243.
  • Campbell DI, Lunn PG & Elia M (2002) Age-related association of small intestinal mucosal enteropathy with nutritional status in rural Gambian children. British Journal of Nutrition 88, 499505.
  • Campbell DI, Murch SH, Ellia M et al. (2003) Chronic T cell-mediated enteropathy in rural West African children: relationship with nutritional status and small bowel function. Pediatric Research 54, 306311.
  • Darveau RP, Tanner A & Page RC (1997) The microbial challenge in periodontitis. Periodontology 2000 14, 1232.
  • Davies-Adetugbo AA (1996) Promotion of breastfeeding in the community: impact of health education programme in rural communities in Nigeria. Journal of Diarrhoeal Disease Research 14, 511.
  • Dinarello CA (1999) Interleukin-18. Methods 19, 121132.
  • Eaton AD, Xu D & Garside P (2003) Administration of exogenous interleukin-18 and interleukin-12 prevents the induction of oral tolerance. Immunology 108, 196203.
  • Enwonwu CO (1972) Epidemiological and biochemical studies of necrotizing ulcerative gingivitis and noma (cancrum oris) in Nigerian children. Archives of Oral Biology 17, 13571372.
  • Enwonwu CO (1973) Influence of socio-economic conditions on dental development in Nigerian children. Archives of Oral Biology 18, 95107.
  • Enwonwu CO (1995) Noma: a neglected scourge of children in sub-Saharan Africa. Bulletin of the World Health Organization 73, 541545.
  • Enwonwu CO, Falkler WA, Jr, Idigbe EO et al. (1999) Pathogenesis of oro-facial gangrene (noma): confounding interactions of malnutrition and infection. American Journal of Tropical Medicine and Hygiene 60, 223232.
  • Enwonwu CO, Falkler WA & Idigbe EO (2000) Oro-facial gangrene (noma/cancrum oris): pathogenetic mechanisms. Critical Reviews in Oral Biology and Medicine 11, 159171.
  • Evrard L, Laroque G, Glineur R & Daeemans P (1996) Noma: clinical and evolutive aspect. Acta Stomatologica Belgica 93, 1720.
  • Falkler WA, Enwonwu CO & Idigbe EO (1999a) Isolation of Fusobacterium necrophorum from noma (cancrum oris). American Journal of Tropical Medicine and Hygiene 60, 150156.
  • Falkler WA, Enwonwu CO & Idigbe EO (1999b) Microbiological understandings and mysteries of noma. Oral Diseases 5, 150155.
  • Fernandez ID, Himes JH & de Onis M (2002) Prevalence of nutritional wasting in populations: building explanatory models using secondary data. Bulletin of the World Health Organization 80, 282291.
  • Fieger A, Marck KW, Busch R & Schmidt A (2003) An estimation of the incidence of noma in north-west Nigeria. Tropical Medicine and International Health 8, 402407.
  • Filteau SM (2000) Role of breast feeding in managing malnutrition and infectious disease. Proceedings of the Nutrition Society 59, 565572.
  • Idigbe EO, Enwonwu CO & Falkler WA (1999) Living conditions of children at risk for noma. Oral Diseases 5, 156162.
  • Kashiwamura S-I, Ueda H & Okamura H (2002) Roles of interleukin-18 in tissue destruction and compensatory reactions. Journal of Immunotherapy 25 (Suppl. 1), S4S11.
  • Lunn PG (2002) Growth retardation and stunting of children in developing countries. British Journal of Nutrition 88, 109110.
  • Lunn PG, Northrop-Clewes CA & Downes RM (1991) Intestinal permeability, mucosal injury and growth faltering in Gambian infants. Lancet 338, 907910.
  • Marck KW (2003) A history of noma, the ‘face of poverty’. Plastic and Reconstructive Surgery 111, 17021707.
  • Monteleone G, Trapasso F, Parello T et al. (1999) Bioactive IL-18 expression is up-regulated in Crohn's disease. Journal of Immunology 163, 143147.
  • Nagamine Y, Hayano M, Kashiwamura S-I et al. (2003). Involvement of interleukin-18 in severe Plasmodium falciparum malaria. Transactions of the Royal Society of Tropical Medicine and Hygiene 97, 236241.
  • NCHS (1977) Growth Curves for Children from Birth to 18 years. United States Department of Health, Education and Welfare, Washington, DC. DHEW Publications PHS, 78-1650.
  • Nwankwo BO & Brieger WR (2002) Exclusive breastfeeding is undermined by use of other liquids in rural southwestern Nigeria. Journal of Tropical Pediatrics 48, 109112.
  • Oberholzer A, Steckholzer U, Okamura H, Kurimoto M, Trentz O & Ertel W (1998) Increased circulating levels of interleukin-18 during severe sepsis in humans. Surgical Forum XLIX, 8889.
  • Obiechina AE, Arotiba JT & Fasola AO (2002) Cancrum oris (noma): level of education and occupation of parents of affected children in Nigeria. Odoto-Stomatologie Tropicale 90, 1114.
  • Okada H, Sato TA, Katayama A et al. (2001) Comparative analysis of host responses related to immunosuppression between measles patients and vaccine recipients with live attenuated measles vaccines. Archives of Virology 146, 859874.
  • Okamura H, Tsutsui H, Kashiwamura S-I, Yoshimoto T & Nakanishi K (1998) Interleukin-18: a novel cytokine that augments both innate and acquired immunity. Advances in Immunology 70, 281312.
  • de Onis M (2001) Child growth and development. In: Nutrition and Health in Developing Countries (eds RDSemba & MWBloem) Humana Press, Inc, Totowa, NJ, pp. 7191.
  • de Onis M & Blosner M (2003) The World Health Organization Global Database on child growth and malnutrition: methodology and applications. International Journal of Epidemiology 32, 518526.
  • de Onis M, Monteiro C, Akre J & Clugston G (1993) The worldwide magnitude of protein-energy malnutrition: an overview from the WHO Global Database on Child Growth. Bulletin of the World Health Organization 71, 703712.
  • Price JS, Oyajobi BO & Russell RGG (1994) The cell biology of bone growth. European Journal of Clinical Nutrition 48 (Suppl. 1), S131S149.
  • Ransome-Kuti O (1985) Intra-uterine growth, birthweights and maturity of the African newborn. Acta Pediatrica Scandinavica, Supplement 319, 95101.
  • Rehan NE & Tafida DS (1981) Low birthweight in Hausa infants. Nigerian Journal of Paediatrics 8, 3539.
  • Rice AL, Sacco L, Hyder A & Black RE (2000) Malnutrition as an underlying cause of childhood deaths associated with infectious diseases in developing countries. Bulletin of the World Health Organization 78, 12071221.
  • Rouabhia M, Ross G, Page N & Chakir J (2002) Interleukin-18 and gamma interferon production by oral epithelial cells in response to exposure to Candida albicans or lipopolysaccharide stimulation. Infection and Immunity 70, 70737080.
  • Sandros J, Karlsson C, Lappin DF, Madianos PN, Kinane DF & Papapanou PN (2000) Cytokine responses of oral epithelial cells to Porph yearsomonas gingivalis infection. Journal of Dental Research 79, 18081814.
  • Sauerwein RW, Mulder JA, Mulder L et al. (1997) Inflammatory mediators in children with protein-energy malnutrition. American Journal of Clinical Nutrition 65, 15341539.
  • Solomons NW (2003) Environmental contamination and chronic inflammation influence human growth potential. Journal of Nutrition 133, 1237.
  • Solomons NW, Mazarigos M, Brown KH & Klassing K (1993) The underprivileged, developing country child: environmental contamination and growth failure revisited. Nutrition Review 51, 327332.
  • Stephensen CB (1999) Burden of infection on growth failure. Journal of Nutrition 129, 534S538S.
  • Sugawara S, Uehara A, Nochi T et al. (2001) Neutrophil proteinase 3-mediated induction of bioactive IL-18 secretion by human oral epithelial cells. Journal of Immunology 167, 65686575.
  • Tempest MN (1966) Cancrum oris. British Journal of Surgery 53, 949969.
  • Thurnham DL, Northrop-Clewes CA, McCullough FSW, Das BS & Lunn PG (2000) Innate immunity, gut integrity and vitamin A in Gambian and Indian infants. Journal of Infectious Disease 182, S23S28.