Risk factors for noma disease: a 6-year, prospective, matched case-control study in Niger.

Noma is a poorly studied disease that leads to severe facial tissue destruction in children in developing countries, but the cause remains unknown. We aimed to identify the epidemiological and microbiological risk factors associated with noma disease.



We did a prospective, matched, case-control study in Niger between Aug 1, 2001, and Oct 31, 2006, in children younger than 12 years to assess risk factors for acute noma. All acute noma cases were included and four controls for each case were matched by age and home village. Epidemiological and clinical data were obtained at study inclusion. We undertook matched-paired analyses with conditional logistic regression models.



We included 82 cases and 327 controls. Independent risk factors associated with noma were: severe stunting (odds ratio [OR] 4·87, 95% CI 2·35-10·09) or wasting (2·45, 1·25-4·83); a high number of previous pregnancies in the mother (1·16, 1·04-1·31); the presence of respiratory disease, diarrhoea, or fever in the past 3 months (2·70, 1·35-5·40); and the absence of chickens at home (1·90, 0·93-3·88). After inclusion of microbiological data, a reduced proportion of Fusobacterium (4·63, 1·61-13·35), Capnocytophaga (3·69, 1·48-9·17), Neisseria (3·24, 1·10-9·55), and Spirochaeta in the mouth (7·77, 2·12-28·42), and an increased proportion of Prevotella (2·53, 1·07-5·98), were associated with noma. We identified no specific single bacterial or viral pathogen in cases.



Noma is associated with indicators of severe poverty and altered oral microbiota. The predominance of specific bacterial commensals is indicative of a modification of the oral microbiota associated with reduced bacterial diversity.



Gertrude Hirzel Foundation.

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title: Bacterial Diversity in Oral Samples of Children in Niger with Acute Noma, Acute Necrotizing Gingivitis, and Healthy Controls
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title: Power calculations for matched case-control studies.
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Simulation studies.



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title: Noma (cancrum oris): questions and answers.
abstract: Noma (cancrum oris) is an infectious disease which destroys the oro-facial tissues and other neighboring structures in its fulminating course. It affects predominantly children aged 2-16 years in sub-Saharan Africa where the estimated frequency in some communities may vary from one to seven cases per 1000 children. The key risk factors are poverty, malnutrition, poor oral hygiene, deplorable environmental sanitation, close residential proximity to livestock, and infectious diseases, particularly measles. Malnutrition acts synergistically with endemic infections in promoting an immunodeficient state, and noma results from the interaction of general and local factors with a weakened immune system as the common denominator. Acute necrotizing gingivitis (ANG) is considered the antecedent lesion. Current studies suggest that evolution of ANG to noma requires infection by a consortium of microorganisms with Fusobacterium necrophorum and Prevotella intermedia as the suspected key players. Without appropriate treatment, mortality rate is 70-90%. Survivors suffer the two-fold affliction of oro-facial disfigurement and functional impairment. Reconstructive surgery of the resulting deformity is time-consuming and financially prohibitive for the victims who are poor.

title: Novel Microarray Design Strategy To Study Complex Bacterial Communities
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title: Inflammatory cytokine profile and circulating cortisol levels in malnourished children with necrotizing ulcerative gingivitis.
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title: Epidemiological and biochemical studies of necrotizing ulcerative gingivitis and noma (cancrum oris) in Nigerian children.
abstract: Epidemiological and biochemical studies were carried out on Nigerian children during the period 1963–1965. The studies were undertaken to determine the role of oral hygiene and the major indices of socio-economic status in the patterns of distribution of necrotizing ulcerative gingivitis and the oro-facial lesion of noma. A total of 1068 children aged 0–10 yr and drawn from educated well-to-do familes, under-privileged village communities and patients hospitalized for treatment of malnutrition and/or cancrum oris formed the sample material. Necrotizing ulcerative gingivitis, which is very rarely seen in children in developed countries, was frequently encountered in Nigerian children and showed a peak age incidence around 2–6 yr. Necrotizing ulcerative gingivitis in Nigeria was found to be a disease of the low socio-economic group. While no case of the lesion was encountered in the high social class children, underprivileged Osegere village children with borderline malnutrition showed an incidence of 15 per cent, and the incidence rose to 27 per cent in hospitalized cases of severe protein-calorie malnutrition. All 69 cases of noma seen were miserably malnourished as revealed by biochemical, clinical and dietary evaluations. The low social group children had poor oral hygiene status compared with their well-fed high socio-economic group counterparts, but there was evidence from some cases of necrotizing ulcerative gingivitis and noma that the status of oral hygiene was not enough to explain the presence of these lesions in only the poor underprivileged communities. Findings of this study have been evaluated in light of the high physiological and metabolic activities of oral tissues and the importance of adequate supply of dietary nutrients for the maintenance of structural and functional integrity of oral tissues.

title: Maternal and child nutrition in Sub-Saharan Africa: challenges and interventions
abstract: Women of child-bearing age (especially pregnant and lactating women), infants and young children are in the most nutritionally-vulnerable stages of the life cycle. Maternal malnutrition is a major predisposing factor for morbidity and mortality among African women. The causes include inadequate food intake, poor nutritional quality of diets, frequent infections and short inter-pregnancy intervals. Evidence for maternal malnutrition is provided by the fact that between 5 and 20% of African women have a low BMI as a result of chronic hunger. Across the continent the prevalence of anaemia ranges from 21 to 80%, with similarly high values for both vitamin A and Zn deficiency levels. Another challenge is the high rates of HIV infection, which compromise maternal nutritional status. The consequences of poor maternal nutritional status are reflected in low pregnancy weight gain and high infant and maternal morbidity and mortality. Suboptimal infant feeding practices, poor quality of complementary foods, frequent infections and micronutrient deficiencies have largely contributed to the high mortality among infants and young children in the region. Feeding children whose mothers are infected with HIV continues to remain an issue requiring urgent attention. There are successful interventions to improve the nutrition of mothers, infants and young children, which will be addressed. Interventions to improve the nutrition of infants and young children, particularly in relation to the improvement of micronutrient intakes of young children, will be discussed. The recent release by WHO of new international growth standards for assessing the growth and nutritional status of children provides the tool for early detection of growth faltering and for appropriate intervention.

title: Human Herpesviridae in acute necrotizing ulcerative gingivitis in children in Nigeria.
abstract: Herpesviruses have been implicated in the pathogenesis of human periodontitis. The present study investigated whether herpesviruses are present in the lesions of acute necrotizing ulcerative gingivitis. Sixty-two Nigerian children, aged 3-14 years, were studied. Twenty-two children had acute necrotizing ulcerative gingivitis and were also malnourished, 20 exhibited no acute necrotizing ulcerative gingivitis but were malnourished and 20 were free of acute necrotizing ulcerative gingivitis and in a good nutritional state. Polymerase chain reaction methods were used to determine the presence of human cytomegalovirus (HCMV), Epstein-Barr virus type 1 and type 2 (EBV-1, EBV-2), herpes simplex virus (HSV), human herpes virus 6 (HHV-6), human papilloma virus and human immunodeficiency virus type 1 in crevicular fluid specimens collected by paper points. Of the 22 acute necrotizing ulcerative gingivitis patients, 15 (68%) revealed viral infection and 8 (36%) viral coinfection. Thirteen (59%) acute necrotizing ulcerative gingivitis patients demonstrated HCMV, 6 (27%) EBV-1, 5 (23%) HSV and 1 (5%) HHV-6. Only 2 (10%) subjects from each group not affected by acute necrotizing ulcerative gingivitis showed viral presence, and no control subject revealed viral coinfection. These findings suggest that HCMV and possibly other herpesviruses contribute to the onset and/or progression of acute necrotizing ulcerative gingivitis in malnourished Nigerian children.

title: Oro-facial gangrene (noma/cancrum oris): pathogenetic mechanisms.
abstract: Cancrum oris (Noma) is a devastating infectious disease which destroys the soft and hard tissues of the oral and para-oral structures. The dehumanizing oro-facial gangrenous lesion affects predominantly children ages 2 to 16 years, particularly in sub-Saharan Africa, where the estimated frequency in some communities varies from 1 to 7 cases per 1000 population. The risk factors are poverty, malnutrition, poor oral hygiene, residential proximity to livestock in unsanitary environments, and infectious diseases, particularly measles and those due to the herpesviridae. Infections and malnutrition impair the immune system, and this is the common denominator for the occurrence of noma. Acute necrotizing gingivitis (ANG) and oral herpetic ulcers are considered the antecedent lesions, and ongoing studies suggest that the rapid progression of these precursor lesions to noma requires infection by a consortium of micro-organisms, with Fusobacterium necrophorum (Fn) and Prevotella intermedia (Pi) as the suspected key players. Additional to production of a growth-stimulating factor for Pi, Fn displays a classic endotoxin, a dermonecrotic toxin, a cytoplasmic toxin, and a hemolysin. Without appropriate treatment, the mortality rate from noma is 70-90%. Survivors suffer the two-fold afflictions of oro-facial mutilation and functional impairment, which require a time-consuming, financially prohibitive surgical reconstruction.

title: Prevalent Bacterial Species and Novel Phylotypes in Advanced Noma Lesions
abstract: The purpose of this study was to determine the bacterial diversity in advanced noma lesions using culture-independent molecular methods. 16S ribosomal DNA bacterial genes from DNA isolated from advanced noma lesions of four Nigerian children were PCR amplified with universally conserved primers and spirochetal selective primers and cloned into Escherichia coli. Partial 16S rRNA sequences of approximately 500 bases from 212 cloned inserts were used initially to determine species identity or closest relatives by comparison with sequences of known species or phylotypes. Nearly complete sequences of approximately 1,500 bases were obtained for most of the potentially novel species. A total of 67 bacterial species or phylotypes were detected, 25 of which have not yet been grown in vitro. Nineteen of the species or phylotypes, including Propionibacterium acnes, Staphylococcus spp., and the opportunistic pathogens Stenotrophomonas maltophilia and Ochrobactrum anthropi were detected in more than one subject. Other known species that were detected included Achromobacter spp., Afipia spp., Brevundimonas diminuta, Capnocytophaga spp., Cardiobacterium sp., Eikenella corrodens, Fusobacterium spp., Gemella haemoylsans, and Neisseria spp. Phylotypes that were unique to noma infections included those in the genera Eubacterium, Flavobacterium, Kocuria, Microbacterium, and Porphyromonas and the related Streptococcus salivarius and genera Sphingomonas and Treponema. Since advanced noma lesions are infections open to the environment, it was not surprising to detect species not commonly associated with the oral cavity, e.g., from soil. Several species previously implicated as putative pathogens of noma, such as spirochetes and Fusobacterium spp., were detected in at least one subject. However, due to the limited number of available noma subjects, it was not possible at this time to associate specific species with the disease.

title: Isolation of Fusobacterium necrophorum from cancrum oris (noma).
abstract: A study of the predominant microflora in active sites of noma (cancrum oris) lesions was carried out in eight noma patients 3-15 years of age in Sokoto State in northwestern Nigeria. Paper point sampling and conventional anaerobic microbiologic techniques were used. Fusobacterium necrophorum was recovered from 87.5% of the noma lesions. Oral microorganisms included Prevotella intermedia, alpha-hemolytic streptococci, and Actinomyces spp. which were isolated from 75.0%, 50.0%, and 37.5% of the patients, respectively. Peptostreptococcus micros, Veillonella parvula, Staphylococcus aureus, and Pseudomonas spp. were each recovered from one lesion. The F. necrophorum and P. intermedia isolates were tested for antibiotic sensitivity to clindamycin, tetracycline, metronidazole, and penicillin using the E-test, and all strains were observed to be sensitive to all of the antibiotics tested with the exception of one strain of P. intermedia, which showed resistance to penicillin. The first reported isolation from human noma lesions of F. necrophorum, a pathogen primarily associated with animal diseases, may have important etiologic and animal transmission implications.

title: Bacterial specificity in adult periodontitis. A summary of recent work.
abstract: 3 studies investigated the importance of Actinobacillus actinomycetemcomitans, Bacteroides gingivalis and Bacteroides intermedius in progressive adult periodontitis. A total of 196 adults with advanced periodontitis and 475 periodontal sites were examined. The periodontal disease activity was assessed by changes in probing periodontal attachment level and crestal alveolar bone level. The composition of the subgingival microflora was determined by nonselective and selective culturing and indirect immunofluorescence of direct smears. A. actinomycetemcomitans occurred in 50% of progressing lesions and in only 6% of nonprogressing sites. B. gingivalis was detected in 42-52% of progressing lesions and in 14% of nonprogressing sites. The median B. gingivalis recovery in culture-positive sites was more than 10-fold higher in progressing than in nonprogressing sites. B. intermedius was recovered from 59-89% of progressing lesions and from 36-53% of nonprogressing sites. B. intermedius averaged 5-10 higher recovery in infected progressing lesions than in infected nonprogressing sites. 1 progressing lesion only failed to reveal any of the above organisms. Assessment of the overall results indicates that A. actinomycetemcomitans, B. gingivalis and B. intermedius are major suspected pathogens in destructive periodontal disease in adults.

title: In vivo cleavage of immunoglobulin A1 by immunoglobulin A1 proteases from Prevotella and Capnocytophaga species.
abstract: Immunoglobulin A1 (IgA1) proteases secreted by oral Prevotella and Capnocytophaga species specifically cleave IgA1 at the same peptide bond in the hinge region, leaving intact monomeric Fab and Fc fragments. Assuming that Prevotella- and Capnocytophaga-induced Fab fragments of IgA1 expose a specific immunogenic neoepitope at the cleavage site, we established an enzyme-linked immunosorbent assay to measure human serum antibodies to this neoepitope as indirect evidence of in vivo activity of Prevotella and Capnocytophaga IgA1 proteases. The assay used a monoclonal antibody with specificity for the neoepitope, and the ability to block binding of the monoclonal antibody to the neoepitope was investigated. Absorption of sera with Prevotella melaninogenica-induced Fab fragments of IgA1 resulted in removal of antibodies blocking binding of the monoclonal antibody, whereas absorption with Fab fragments induced by bacterial IgA1 proteases of other cleavage specificities did not remove blocking antibodies. Consequently, we assume that the antibodies detected had been induced by a neoepitope an the Fab fragment of IgA1 exposed exclusively after cleavage with IgA1 proteases from Prevotella and Capnocytophaga, indicating in vivo activity of these IgA1 proteases. Evidence, though indirect, of in vivo activity of Prevotella and Capnocytophaga IgA1 proteases was present in 42 of 92 sera examined and in a significantly higher proportion of sera from adults with periodontal disease compared with control individuals. No correlation with disease was observed for the juvenile periodontitis groups.

title: Recovery of anaerobic bacteria from four children with postthoracotomy sternal wound infection.
abstract: The cases of 4 children who developed postthoracotomy sternal wound infection caused by anaerobic bacteria are presented. The predominate anaerobes were Peptostreptococcus species and pigmented Prevotella species. Polymicrobial infection was present in all cases, and aerobic bacteria also were recovered in 2 instances. All patients responded to surgical debridement and antimicrobials effective against the isolated aerobic and anaerobic bacteria. These findings highlight the potential importance of anaerobic bacteria in postthoracotomy sternal wound infection.

title: Bacteriology of histopathologically defined appendicitis in children.
abstract: Acute appendicitis is the most common surgical emergency in childhood. However, the pathogenesis and detailed microbiology are obscure.



To determine in detail the bacterial etiology of appendicitis in children in relation to the histologic tissue pathology.



Tissue samples obtained at surgery from 41 children with suspected acute appendicitis were examined histologically and by culture for aerobic and anaerobic bacteria. The patients were analyzed according to histopathologic and clinical findings.



Aerobic and anaerobic species were isolated from 40 of 41 (98%) samples; on average, 14.1 isolates per specimen (10.4 anaerobes and 3.7 aerobes). Specimens from patients with gangrenous appendices yielded significantly higher numbers of anaerobic isolates per specimen than did specimens from patients with healthy appendices (11.7 vs. 7.7; P < 0.01). Bacteria belonging to the Bacteroides fragilis group were the most frequently isolated anaerobic microorganisms (95%). Other organisms frequently isolated in all histology groups were Peptostreptococcus micros (66%), Bilophila wadsworthia (63%), Fusobacterium nucleatum (44%), Eggerthella lenta (44%) and a hitherto undescribed bile-resistant, pigment-producing Gram-negative rod (41%). Of the aerobes Escherichia coli (88%) and Streptococcus anginosus group (former Streptococcus "milleri" group) organisms (61%) were the most frequent findings.



The shift from histologically normal toward gangrenous appendices was clearly associated with markedly elevated anaerobic bacterial counts in terms of species. The unusually high frequencies of B. wadsworthia (75%) and the hitherto undescribed bile-resistant, pigment-producing Gram-negative rod (56%) in gangrenous appendices represent unique and different findings from those reported in adults.

title: Microbial composition of supra- and subgingival plaque in subjects with adult periodontitis.
abstract: The purpose of the present study was to compare and relate the microbial composition of supra and subgingival plaque in 23 adult periodontitis subjects (mean age 51 +/- 14 years).



A total of 1,170 samples of supra and subgingival plaque were collected from the mesial aspect of every tooth (up to 28 supra and 28 subgingival samples) from each subject and evaluated for the presence and levels of 40 bacterial taxa using whole genomic DNA probes and checkerboard DNA-DNA hybridization. Clinical assessments including dichotomous measures of gingival redness, bleeding on probing, plaque accumulation and suppuration, as well as duplicate measures of pocket depth and attachment level, were made at 6 sites per tooth. The counts (levels), % DNA probe count (proportion) and % of sites colonized (prevalence) of each species in supra and separately in subgingival plaque were computed for each subject. Significance of differences between supra and subgingival plaque for each species was sought using the Wilcoxon signed ranks test and adjusted for multiple comparisons.



All 40 taxa were detected in both supra and subgingival plaque. Actinomyces species were the most prevalent taxa in both habitats. 75 to 100% of supra and 62 to 100% of subgingival sites were colonized by at least one of the 5 Actinomyces species. Supragingival samples exhibited significantly higher counts of Actinomyces naeslundii genospecies 1, Actinomyces israelii, Actinomyces odontolyticus, Neisseria mucosa, Streptococcus gordonii, Capnocytophaga ochracea and Capnocytophaga sputigena when compared with mean counts in subgingival samples taken from the same tooth surfaces. Subgingival plaque samples presented significantly higher counts of Prevotella nigrescens, Prevotella intermedia, Bacteroides forsythus and Porphykromonas gingivalis. Subgingival samples exhibited a significantly higher proportion of "red" and "orange complex" species, while supragingival plaque exhibited higher proportions of "green" and "purple" complex species as well as Actinomyces species. Suspected periodontal pathogens could be detected in supragingival plaque from sites where subgingival samples were negative for the same species.



The data indicate that supragingival plaque can harbor putative periodontal pathogens, suggesting a possible rôle of this environment as a reservoir of such species for the spread or reinfection of subgingival sites.

title: Reduction in child mortality in Niger: a Countdown to 2015 country case study
abstract: The Millennium Development Goal 4 (MDG 4) is to reduce by two-thirds the mortality rate of children younger than 5 years, between 1990 and 2015. The 2012 Countdown profile shows that Niger has achieved far greater reductions in child mortality and gains in coverage for interventions in child survival than neighbouring countries in west Africa. Countdown therefore invited Niger to do an in-depth analysis of their child survival programme between 1998 and 2009.



We developed new estimates of child and neonatal mortality for 1998-2009 using a 2010 household survey. We recalculated coverage indicators using eight nationally-representative surveys for that period, and documented maternal, newborn, and child health programmes and policies since 1995. We used the Lives Saved Tool (LiST) to estimate the child lives saved in 2009.



The mortality rate in children younger than 5 years declined significantly from 226 deaths per 1000 livebirths (95% CI 207-246) in 1998 to 128 deaths (117-140) in 2009, an annual rate of decline of 5·1%. Stunting prevalence decreased slightly in children aged 24-35 months, and wasting declined by about 50% with the largest decreases in children younger than 2 years. Coverage increased greatly for most child survival interventions in this period. Results from LiST show that about 59,000 lives were saved in children younger than 5 years in 2009, attributable to the introduction of insecticide-treated bednets (25%); improvements in nutritional status (19%); vitamin A supplementation (9%); treatment of diarrhoea with oral rehydration salts and zinc, and careseeking for fever, malaria, or childhood pneumonia (22%); and vaccinations (11%).



Government policies supporting universal access, provision of free health care for pregnant women and children, and decentralised nutrition programmes permitted Niger to decrease child mortality at a pace that exceeds that needed to meet the MDG 4.



Bill & Melinda Gates Foundation; World Bank; Governments of Australia, Canada, Norway, Sweden, and the UK; and UNICEF.