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Invasive meningococcal infections remain an important cause of death in children. In addition, malnutrition has been classically associated with increased severity of infectious diseases. However, in our experience lethal meningococcaemia in clinically malnourished children is extremely rare. Our purpose was to determine whether there is an association between nutritional status and outcome in children with invasive meningococcal infection.
We carried out an observational study and prospectively determined anthropometrical parameters in 127 children aged 1 month to 4 years with invasive meningococcal infection seen in our inpatient facilities from August 1999 to May 2004. Severity and survival were the clinical end points analysed.
Children with severe disease had higher weight for age (1.02 vs −0.19) and height for age (1.12 vs −0.58) z scores than those with non‐severe disease. Non‐survivors had higher weight for age (0.90 vs −0.16) and height for age (0.73 vs −0.57) z scores than survivors. Clinical and biological variables usually accepted as predictors of high mortality or severity in patients with meningococcal infection were not significantly associated with weight for age and height for age z scores.
In the present prospective series of children with invasive meningococcal disease, severity and death were linked to anthropometrical parameters and seemed to be associated with a very good nutritional status, which confirmed our previous uncontrolled observations.
Invasive meningococcal infections remain an important cause of morbidity and death in children, with case‐fatality rates ranging from 6% to 15%.1,2 The reasons why only some individuals develop the most lethal form of invasive disease (ie, fulminant meningococcaemia) are not fully understood.1,3 Some inherited conditions, such as genetic polymorphisms in mannosa‐binding lectin and tumour necrosis factor (TNF) promoter, and FC‐γ IIa heterogeneity and complement deficiencies (reviewed in Emonts et al4), have been linked to increased frequency or severity of cases.
Malnutrition has been classically associated with increased frequency and severity of infectious diseases, particularly in the 0–4‐year‐old age group.5 However, this was not our clinical impression during many years of work with patients suffering and dying from meningococcal infection.6 In our experience, infants and small children dying from meningococcaemia normally had a very good nutritional appearance.
In order to confirm the association between a good nutritional appearance and death from meningococcal infection, we retrospectively reviewed the medical records of 74 children aged 1 month to 4 years with proven meningococcal infections (seven deaths) who were assisted in our hospital during a 2‐year period. Children who died were stated as being clinically well‐nourished and there were no deaths in five children with a weight for age z score less than −2. However, in severely ill or dying patients, weight was frequently a rough estimation and heights were rarely obtained. We therefore initiated the present prospective study to examine differences in mortality and severity as clinical end points, as a function of weight and height for age, in 1‐month to 4‐year‐old children with meningococcal infections.
Patients aged 1 month to 4 years with a clinical diagnosis of meningococcal meningitis or sepsis2 who were assisted in the Sor María Ludovica Children's Hospital in La Plata, Argentina, since August 1999 were prospectively included in the study and were considered probable cases. The study was stopped in May 2004 because a double blinded, placebo‐controlled trial which would modify the treatment of severe cases was initiated. Patients were retained in the study only if the discharge diagnosis was also consistent with meningococcal disease. Efforts directed at demonstrating the aetiology of the infection or isolating the causative organism included blood cultures, cerebrospinal fluid (CSF) cultures, direct staining of CSF and slide tests (Slidex meningite kit, bioMérieux, Marcy l'Etoile, France). Individuals with Gram‐negative cocci in CSF staining or meningococcal detection by at least one of these procedures were considered to have proven meningococcal disease.3 Leukocyte and platelet counts in peripheral blood, cellularity of the CSF, blood pressure, inotropics and fluid needs, peripheral blood refill and the presence of petechiae or echymosis were measured on arrival at the inpatient services of the Sor María Ludovica Children's Hospital at La Plata. Need for intensive care and days spent in the intensive care unit (ICU) were recorded.
Patients who died, had amputations or required extensive reparative surgery were considered as having severe meningococcal infection.
Weight, supine length, skinfold thickness and mid‐upper arm circumference were obtained. Weight was measured on arrival (before or at the same time that resuscitation fluid administration was initiated) on a standard scale with an accuracy of 100 g. Length was determined by one of us (NP) with a rigid wooden device with an accuracy of 0.5 cm. Skinfold thickness and mid‐upper arm circumference were determined by a trained observer (NO) using the standard procedure7 before prolonged intensive resuscitation procedures were performed. Results were transferred to a centile table7 and expressed as centile values.
Weight for age, height for age, weight for height z scores and body mass index (BMI) were calculated with Siscres software according to international standards.8
Statistical procedures were performed using SPSS 9.0 for Windows. Comparisons of continuous data between dichotomised categories were made using the Mann Whitney test. Correlations were calculated using the non‐parametric Spearman's correlation coefficient. Proportions were compared by the χ2 test. Comparisons of outcomes between groups of at‐risk individuals were made with Fisher's exact test, using two‐by‐two tables. The p values obtained were two tailed.
Informed consent was obtained from the children's parents or guardians. Ethical approval was obtained from the local independent ethics committee. Scientific approval was obtained from appropriate local authorities.
A total of 131 white children aged 1 month to 4 years were seen in our inpatient facilities with suspected or proven meningococcal meningitis or sepsis. On arrival, 36 children had a clinical diagnosis of meningococcal infection but without confirmation criteria (probable cases). Four of these patient received another diagnosis during their hospital stay and were excluded from the analysis. A total of 95 children satisfied the criteria of proven meningococcal infection.
Thirteen children died and two children had fingers amputated and needed extensive reparative surgery comprising multiple skin grafts. Fifteen children were therefore considered as having severe infection. Two of the non‐survivors died before any anthropometrical parameters could be obtained and were excluded from the analysis; both were stated to be clinically well‐nourished on admission.
Clinical and biological findings at admission in severe and non‐severe cases are shown in table 11.
Only clinical and biological variables usually accepted as markers of poor outcome9,10 were significantly associated with severe infection in the present series of patients. Clinical and biological variables were identical in children with suspected or proven meningococcal infection (data not shown).
When the anthropometrical data of severe and non‐severe patients were compared, patients with severe disease had higher weight for age z scores and were significantly taller than patients with non‐severe disease. Children with severe infection had higher mid‐upper arm circumference measurements than those with non‐severe infection, and a similar but non‐significant trend was also present for skinfold thickness (table 22).
When non‐survivors and survivors were compared, non‐survivors had higher weight for age (0.90 vs −0.16; p 0.025) and height for age (0.73 vs −0.57; p 0.012) z scores than survivors. As seen in table 22,, BMI was significantly higher in those with severe than in those with non‐severe disease. Weight for height z scores were also higher in those with severe disease, but differences did not reach statistical significance. The relative scarcity of data on skinfolds and arm circumference should be considered when analysing the results. This shortage is due to the fact that it was difficult for a single trained person to evaluate patients before prolonged intensive resuscitation procedures were begun. The distribution of weight for age and height for age of severe and non‐severe cases is shown in fig 11.
In the post hoc analysis, we searched for markers, conditions or other variables related to weight and height for age, that may actually be responsible for the association between weight and height for age and severity. We therefore determined the correlation of weight and height for age and all variables significantly associated with severity listed in table 11.. None of the analysed variables was correlated with both weight for age and height for age z scores (data not shown).
We also searched for an association of weight and height for age and the following new variables: need to be transferred to an ICU (an indirect indicator of severity), number of persons living in the house (as an indicator of household crowding) and laboratory confirmation of meningococcal infection (to rule out bias induced by misdiagnoses). Twenty two children needed to be transferred to an ICU. Medians of weight for age z scores appeared to be higher in children who required ICU support compared with medians in children who did not (0.17 vs −0.15, respectively; p=0.08). Medians of height for age z scores were higher in children who required ICU support compared with children who did not (0.37 vs −0.58, respectively; p 0.01). Neither the number of persons living in the house nor laboratory confirmation of meningococcal infection was associated with either weight or height for age z scores (data not shown).
The Sor María Ludovica Children's Hospital in La Plata is a tertiary care hospital and receives more than 50% of patients with invasive meningococcal infections in the province of Buenos Aires. Children with this presumptive diagnosis are frequently referred to us from peripheral centres and, if suitable, receive fluids and parenteral antibiotics (usually a third‐generation cephalosporin) before referral.
Death from meningococcal infection, and particularly from meningococcaemia, is usually a brutal event occurring in formerly healthy infants and children. In addition to previous well‐being, in our personal clinical experience, an excellent nutritional appearance was the rule in babies who died from meningococcaemia; severe meningococcaemia in clinically malnourished children was extremely rare.
In our series of 127 children with meningococcal infection, we have been able to demonstrate a significant difference in weight and height for age in children with severe compared to those with non‐severe disease and between survivors and non‐survivors. These results agreed with our anecdotal observation.
A significant association between death from meningococcal infection and high weight for age has been recently reported by Blanco Quiros et al, who searched retrospectively for parameters associated with poor outcome in 71 Spanish children aged 2 months to 13 years.11 In their series they did not find an association between weight for age and scores of severity obtained on arrival at hospital (Glasgow Scale for Meningococcal Sepsis and the Pediatric Risk of Mortality). Children with higher weight for age had increased fatality rates even when they had similar severity scores on arrival. Unfortunately, height was not obtained.
A major concern in our work is the fact that weight can be modified by infection itself or by resuscitation procedures, and it may represent a bias in that the most severely ill children receive earlier and more aggressive fluid therapy and have a higher frequency of renal impairment, fluid retention or liquid sequestration. This reserve, however, does not apply to length.
When in post hoc analysis we examined the correlation of weight or height for age z scores with other variables, including some considered surrogate markers of severe meningococcal infection,2,9,10 none was found to be significantly associated simultaneously with both weight and height for age z scores. This is in accordance with the findings of Blanco Quiros,11 and suggests that weight and height for age z scores are independently associated with severity.
Our study was designed to prove the association of increased severity of and mortality from invasive meningococcal infection with a good nutritional status; therefore the causes of the phenomenon we describe remain highly speculative. Two main hypotheses could be advanced a priori: (1) anthropometrical parameters truly represent nutritional status, and a better nutritional status increases severity or, conversely, a worse nutritional status protects against severe meningococcal infection; and (2) some other factors related to anthropometrical parameters and/or nutritional status, such as poverty or poverty‐linked conditions, increased exposure to bacteria and endotoxin, overcrowding or even late referral (referral bias), are responsible for the observed phenomenon.
Referral bias seems unlikely. The hospital is situated near the most populated areas of the province. More than 80% of meningitis patients are from the hospital area and referral from other centres is linked to the suspicion or diagnosis of meningococcal disease, regardless of nutritional status. The death of children with severe infection at home or before arrival is another potential source of bias. Death at home is a very infrequent event in the province of Buenos Aires for cultural, social and legal reasons. However, even if we consider such a possibility unlikely, death at home or before arrival cannot be formally excluded from our data.
Even though seriously ill children are not ideal subjects for determining nutritional status, height and weight for age may be easily obtained and remain among the most common indices for assessing nutritional status. The values for weight and height for age of children with non‐severe meningococcal disease were similar to data from a low‐income population of La Plata.12 As seen in fig 11,, the data showed a deviation from the mean towards negative values for height, with near‐normal weight. Similar findings are usually seen in chronically undernourished populations.13 Conversely, children with severe infection showed very good nutritional status, as judged by their high weight and height for age.
It is well established that inflammatory mediators and cytokines are elevated in serum from patients with meningococcal disease, and serum levels correlate with severity of disease.14 In vitro production of inflammatory mediators such as TNF and interleukin‐615 is diminished in malnourished individuals. In our patients, BMI and weight for height, two age‐independent measurements of the relationship between weight and height, seemed to be higher in severe cases. Fat excess may be a proinflammatory condition, and fat tissue may be an important source of TNF and other proinflammatory mediators.16 Therefore, our findings may represent an association between nutritional status and the ability to mount a subnormal, normal or exaggerated inflammatory response.
It is also known that exposure to lipopolysaccharide (LPS) in humans is followed by a so‐called refractory period, defined as a reduced ability to produce TNF or other inflammatory mediators.17 This is also true in patients with meningococcal infection.18 A similar phenomenon of LPS tolerance seems to occur in situations of frequent or continuous exposure to LPS. Continuous exposure of farmers' children to high concentrations of LPS in vivo seems to be associated with diminished TNF production by their mononuclear cells in response to LPS in vitro.19 Increased exposure to bacteria and endotoxin, as a consequence of consumption of contaminated food, is frequently associated with malnutrition and sometimes seems to occur without clinical consequences.20,21 In children with repeated exposure to LPS, a diminished in vivo response to endotoxin may represent an adaptive mechanism (as a “price to pay” for survival), limiting a potent but potentially catastrophic inflammatory response to their dangerous environment.
High rates of meningococcal carriage associated with poverty22 or other poverty‐linked conditions may explain the increased frequency of meningococcal infections in some populations.23,24 It would be interesting to know if case‐fatality rates are linked to anthropometrical parameters within these communities, particularly if children with good and bad nutritional status live close together. The potential possibility and relevance of referral bias should be explored in future population‐based studies controlled for socio‐economic status.
We anticipate that answering the outstanding questions on the relationship between the severity of meningococcal infections and anthropometrical parameters, nutritional status or other related conditions will further contribute to our understanding of the mechanism of sepsis‐induced morbidity and death.
We thank Dr Luis Guimarey, Investigator from the Comisión de Investigaciones Científicas de la Provincia de Buenos Aires and one of the authors of Siscres, for his kind gift of the software.
BMI - body mass index
CSF - cerebrospinal fluid
ICU - intensive care unit
LPS - lipopolysaccharide
TNF - tumour necrosis factor
Competing interests: None declared.