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ORIGINAL STUDIES Influence of Malnutrition on the Course of Childhood Bacterial Meningitis Irmeli Roine, MD,* Gerardo Weisstaub, MD,† Heikki Peltola, MD, and the LatAm Bacterial Meningitis Study Group Background: Malnutrition may be an important cofactor explaining poor outcome of childhood bacterial meningitis (BM) in developing countries. We examined its effect in Latin American children. Methods: The weight-for-age z score was determined for 482 children with BM aged 2 months to 5 years. Normal weight (z score from ⬎⫺1 to ⬍⫹1), underweight (z score ⬍⫺1) and overweight (z score ⬎⫹1) children were compared on admission, in-hospital and at discharge. Using uni- and multivariate analysis, we sought for associations between malnutrition and 3 different outcomes. Results: The mean z score was ⫺0.41 ⫾ 1.54, with a normal distribution. Overall, 260 (54%) patients were of normal weight, 151 (31%) underweight, and 71 (15%) overweight. Compared with others, underweight patients had on admission a lower Glasgow coma score (P ⫽ 0.0006) and cerebrospinal fluid glucose concentration (P ⫽ 0.03), and a slower capillary filling time (P ⫽ 0.02). Their death rate was higher (P ⫽ 0.0004) and they survived with more neurological sequelae (P ⫽ 0.04), but a similar frequency of hearing impairment (P ⬎ 0.05). The odds for death increased 1.98 times by mild (95% confidence interval 关CI兴, 1.03–3.83; P ⫽ 0.04), 2.55 times by moderate (95% CI, 1.05– 6.17; P ⫽ 0.04), and 5.85 times (95% CI, 2.53–13.50; P ⬍ 0.0001) by severe underweight. Overweight was not associated with adverse outcomes (P ⬎ 0.05). Conclusions: Children who are underweight at the time of onset of BM have a substantially increased probability of neurological sequelae and death. Key Words: bacterial meningitis, malnutrition, outcome, childhood infections (Pediatr Infect Dis J 2010;29: 122–125) C hildhood bacterial meningitis remains a major problem globally, despite the virtual vaccine-induced elimination of Haemophilus influenzae type b, and to a lesser extent, pneumococcal meningitis in the industrialized world.1 One of the presumed reasons for its manifest poorer prognosis in developing countries is being underweight, a common companion of poverty.2 Infection and malnutrition are intricately linked.3 In bacterial meningitis, severe underweight increases mortality and neurologic sequelae,4 – 6 but recent data from Angola suggest that its role is smaller than that of impaired consciousness, severe dyspnea, or Accepted for publication March 2, 2009. From the *Faculty of Health Sciences, University Diego Portales, Santiago, Chile; †Instituto de Nutrición y Tecnología de los Alimentos (INTA), University of Chile, Chile; and ‡HUCH Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland. Supported by the Alfred Kordelin, Päivikki and Sakari Sohlberg and Sigfrid Jusélius Funds, and the Foundation for Pediatric Research, Finland. Address for correspondence: Irmeli Roine, MD, Los Misioneros 2237, Providencia, Santiago, Chile. E-mail: [email protected]. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www.pidj.com). Copyright © 2010 by Lippincott Williams & Wilkins ISSN: 0891-3668/10/2902-0122 DOI: 10.1097/INF.0b013e3181b6e7d3 122 | www.pidj.com seizures.6 Little is known of its effect on hearing impairment and virtually nothing about the potential influence of milder forms of underweight. Given that mild and moderate underweight are much more prevalent in Latin America (20% and 5%, respectively) than the severe form (0.5%), they may have great practical importance.7 Besides underweight, overweight causes metabolic changes, and alterations of the inflammatory response.8 In adults, obesity is a risk for survival after acute interventions,9 but its potential effects in childhood bacterial meningitis have not been evaluated. Using prospectively collected data from a large clinical trial,10 our present study examines the influence of different stages of under- and overweight on the course and outcome of childhood bacterial meningitis. Because hearing impairment may be produced by different processes than severe neurologic sequelae and death,11 the 3 outcomes were examined separately. MATERIALS AND METHODS This post hoc analysis comprises children with bacterial meningitis during 1996 to 2003 from 10 centers in Latin America,10 who were weighed on admission, and whose exact date of birth was registered. This data is needed to determine the z score of weight-for-age by the WHO nutritional survey calculator, which has an upper age limit of 5 years.12 Z scores could be determined in 482 (90%) of 536 eligible patients (106 from Argentina, 105 from Ecuador, 104 from Venezuela, 102 from Dominican Republic, and 65 from Paraguay). The patients, treatments, and outcomes have been described in detail earlier.10 In brief, the study was a randomized, double blind clinical trial comparing different adjuvant medications to improve outcome from childhood bacterial meningitis, enrolling clinically suspect cases aged 2 months to 16 years. Of the 482 children included in the present analysis, 210 (44%) children had meningitis caused by Haemophilus influenzae type b, 106 (22%) by Streptococcus pneumoniae, 60 (12%) by Neisseria meningitidis, and 14 (3%) by another organism (5 Salmonella enteritidis, 2 Escherichia coli, 2 Group B streptococcus, 2 H. influenzae type a, 1 Pseudomonas aeruginosa, 1 Staphylococcus aureus, and 1 Acinetobacter spp.). In 92 (19%) cases the etiology remained undisclosed, but the patients fulfilled the predefined criteria of bacterial meningitis.10 Seventy-two of the 482 (15%) children died. Of the 410 survivors, 406 underwent a neurologic (in 2 only severe sequelae were registered) and 396 an audiological evaluation (in 7 only severe impairment was registered) at discharge. “Severe neurologic sequelae” (blindness, quadriplegia, or paresis, hydrocephalus needing a shunt, or severe psychomotor retardation) were found in 39 of 406 (10%) patients, and “any neurologic sequelae” (besides severe sequelae, hemiparesis, monoparesis, moderate psychomotor retardation, or ataxia) in 128 of 404 (32%) patients. Deafness (better ear’s hearing threshold ⱖ80 dBs) was detected in 39 of 396 (10%) patients, and any hearing impairment (better ear’s hearing threshold ⬎40 dBs) in 103 of 389 (26%) patients. (Differences in outcomes by country are detailed in Additional Patient Data Table available in the journal’s editorial office). The Pediatric Infectious Disease Journal • Volume 29, Number 2, February 2010 The Pediatric Infectious Disease Journal • Volume 29, Number 2, February 2010 Statistics A z score, used here to define the child’s weight-for-age, is a measure of how many standard deviation units from the mean a particular value of data lies.12 The nutritional category is defined as normal when the z score is ⱖ⫺1 to ⱕ⫹1.13 Underweight is defined as a z score ⬍⫺1, and subdivided into mild underweight (z score from ⱖ⫺2 to ⬍⫺1), moderate underweight (z score ⱖ⫺3 to ⬍⫺2) and severe underweight (z score ⬍⫺3). Overweight is defined as a z score ⬎⫹1, and subdivided into (simple) overweight (z score ⬎⫹1 to ⱕ⫹ 2), obesity (z score from ⬎⫹ 2 to ⱕ⫹3), and severe obesity (z score ⬎⫹3). For the comparison of the data between normal weight, underweight, and overweight children we used ANOVA for normally distributed, and the Kruskal Wallis test for not normally distributed continuous variables, and the contingency table for nominal variables. The odds ratio (OR) of the different stages of underweight or overweight for death, neurologic, and audiological sequelae were calculated by projecting these against normal weight children using binominal logistic regression. Whether underweight was an independent predictor of death, besides the fundamental influence of the child’s presenting condition,14 and adjuvant treatments, was examined by including the 3 as independent variables in a multivariate logistic regression analysis. To test if the relationship between underweight and death was confounded (eg, erroneously estimated as too high or too low) by the country of origin, or etiology we compared the crude and the adjusted OR. If the crude OR differs from the adjusted OR by 10% or more, there is important confounding.15 The results are given as OR and 95% confidence intervals (95% CI). All P values below 0.05 were taken as significant. RESULTS The weight-for-age z scores of the patients had a normal distribution with a mean ⫾ SD of ⫺0.41 ⫾ 1.54 and a range from ⫹ 4.50 to ⫺8.43. Overall, 260 (54%) patients were of normal weight, 151 (31%) underweight (88 mildly, 34 moderately, and 29 severely) and 71 (15%) overweight (47 mild, 19 obese, and 5 very obese). Percentages of underweight patients by country ranged from 22% in Argentina to 41% in Ecuador and of overweight patients from 6% in Ecuador to 22% in the Dominican Republic (Table, Supplemental Digital Content 1, http://links.lww.com/INF/A190). Compared with the other patients (Table, Supplemental Digital Content 2, http://links.lww.com/INF/A191), the underweight children were younger (P ⫽ 0.01), more often males (P ⫽ 0.003), had more frequently convulsions before admission (P ⫽ 0.03), and their disease was caused more often by “other” etiology (P ⫽ 0.005). Their parents had not noticed signs or symptoms of Malnutrition in Meningitis illness for a longer time (P ⬎ 0.05), but their illness on admission was more severe: the age-adjusted Glasgow coma score (P ⫽ 0.0006) and CSF glucose concentration (P ⫽ 0.03) were lower and the capillary filling time longer (P ⫽ 0.02) than in the other 2 groups. The underweight patients died (P ⫽ 0.0004), and developed any neurologic sequelae (P ⫽ 0.04) more frequently than the 2 other groups, but did not differ in their audiological prognosis (P ⬎ 0.05). The risk of death (Table 1) increased with increasing underweight, being 1.98-fold (95% CI, 1.03–3.83; P ⫽ 0.04) in mild, 2.55-fold (95% CI, 1.05– 6.17; P ⫽ 0.04) in moderate, and 5.85fold (95% CI, 2.53–13.50; P ⬍ 0.0001) in severe underweight. Also severe neurologic sequelae increased in severe underweight (OR, 5.05; 95% CI, 1.59 –16.05; P ⫽ 0.006), but not in its milder forms (P ⬎ 0.05). Underweight remained an independent predictor of death when analyzed together with Glasgow coma score on admission and the adjuvant treatments (OR, 1.95; 95% CI, 1.05–3.62; P ⫽ 0.03, Table 2). The relationship between underweight and death (crude OR, 2.69) was not confounded by country of origin (adjusted OR, 2.49) or etiology (adjusted OR, 2.54). Severe obesity showed a tendency towards increasing mortality (OR, 5.52; 95% CI, 0.88 –34.50; P ⫽ 0.07). Otherwise overweight was not associated with the outcomes (P ⬎ 0.05, data not shown). DISCUSSION Our results show that an underweight child is prone to have a severe form of bacterial meningitis with more sequelae and deaths than his/her normal weight counterparts. Overweight, except possibly extreme obesity, does not seem to play an important role in this regard. Our findings agree with previous data showing that severe underweight increases mortality of bacterial meningitis.4 – 6 In addition, they supply new information on the extent of this influence. Overall, severe underweight increased the risk to die of bacterial meningitis almost 6-fold (OR, 5.85). This is similar to the 5.22-fold increase of death by severe underweight in measles.16 Moderate underweight increased the fatality rate 2.55 times, somewhat less than the 4.24 times for overall mortality from common developing country childhood infections.16 Even mild underweight doubled the mortality of bacterial meningitis (OR, 1.98), as it does in pneumonia (OR, 2.01), and malaria (OR, 2.12).16 The effect of mild underweight is especially important, considering its high prevalence in the less privileged areas of the world; in our series it was twice and 3 times as common as moderate or severe underweight, respectively. Although mild malnutrition can be easily missed if not especially sought for, it has been estimated that TABLE 1. Odds for Adverse Outcome From Bacterial Meningitis in Different Stages of Underweight, Compared to 260 Normal Weight Patients Adverse Outcome Death Severe neurological sequelae Any neurological sequelae Deafness* Any hearing impairment† Mild Underweight, n ⫽ 88 Moderate Underweight, n ⫽ 34 Severe Underweight, n ⫽ 29 z Score ⱖ⫺2 to ⬍⫺1 z Score ⱖ⫺3 to ⬍⫺2 z Score ⬍⫺3 OR 95% CI P OR 95% CI P OR 95% CI P 1.98 1.41 0.81 0.75 0.95 1.03–3.83 0.59 –3.38 0.46 –1.41 0.29 –1.90 0.52–1.76 0.04 0.44 0.46 0.54 0.88 2.55 1.45 1.66 1.01 1.15 1.05– 6.17 0.40 –5.27 0.74 –3.76 0.28 –3.59 0.48 –2.79 0.04 0.57 0.22 0.99 0.75 5.85 5.05 1.43 0.60 0.71 2.53–13.50 1.59 –16.05 0.48 – 4.20 0.08 – 4.74 0.19 –2.63 ⬍0.0001 0.006 0.52 0.62 0.61 *Hearing threshold ⱖ80 dBs in the better ear. † Hearing threshold ⬎40 dBs in the better ear. © 2010 Lippincott Williams & Wilkins www.pidj.com | 123 The Pediatric Infectious Disease Journal • Volume 29, Number 2, February 2010 Roine et al TABLE 2. Multivariate Analysis of the Relationship Between Death From Childhood Bacterial Meningitis and Weight-for-Age, Glasgow Coma Score, and Adjuvant Treatments Death Variable OR 95% CI P Underweight (z score ⬍⫺1), n ⫽ 151* 1.95 1.05–3.62 0.03 Overweight (z score ⬎⫹1), n ⫽ 71* 0.98 0.37–2.60 0.97 Glasgow coma score † 3.26 1.53– 6.95 0.002 12 to 10, n ⫽ 119 11.68 5.36 –25.46 ⬍0.0001 9 to 7, n ⫽ 58† † 34.71 12.49 –96.45 ⬍0.0001 6 or below, n ⫽ 26 Adjuvant treatment ‡ Dexamethasone, n ⫽ 110 0.95 0.43–2.10 0.90 0.76 Dexamethasone ⫹ glycerol, n ⫽ 116‡ 0.88 0.40 –1.95 ‡ Glycerol, n ⫽ 129 0.68 0.30 –1.55 0.35 *Compared to normal weight patients, n ⫽ 260. † Compared to Glasgow coma score of 15 to 13, n ⫽ 262. ‡ Compared to placebo recipients, n ⫽ 127. no less than 83% of the increased mortality from childhood infectious diseases in developing countries is due to its mild-to moderate forms.17 The prognostic relevance of underweight was further underlined in multivariate analysis, which showed that it is an independent predictor of death, besides Glasgow coma score on admission14 and adjuvant treatments. Further, neither the country of origin, nor etiology confounded this result. This differs from the Luanda study,6 where severe underweight lost in prognostic importance when included with other predictors in multivariate analysis. The probable reason for this difference is that the present analysis included all stages of underweight, now recognized to have a notable impact, whereas in the previous analysis moderate and mild underweight were included with the normal weight group. This probably increased the mortality associated with “normal weight,” and thus reduced the difference compared with the severe underweight group. Clearly, underweight, even its mildest stage, is a major factor adding to the poor prognosis of childhood bacterial meningitis in developing countries.2 In comparison, lack of ICU resources or treatment details may be secondary. Malnutrition produces multiple deficiencies of protein, zinc, vitamin A, selenium, and essential fatty acids, and deteriorates the integrity and the function of the majority of the immune mechanisms including physical barriers, complement system, phagocytosis, leptin, and proinflammatory cytokine production and both humoral and cellular immunity.3,8,18 The underweight patient is considered to be an immunocompromised host, who does not necessarily show the usual signs of infection, such as fever. The biochemical and physiological effects of severe underweight are better explored than that of mild and moderate underweight. The pathophysiologic mechanisms which jointly lead to neuronal injury and an adverse outcome from bacterial meningitis are the systemic inflammatory response of the host, stimulation of resident microglia within the CNS by bacterial compounds, and possibly direct toxicity of bacterial compounds on neurons.19 If, how, and to what extent underweight enhances them is not known. Because the malnourished have a reduced capacity of proinflammatory cytokine production,8,19 an enhanced host response through increased cytokine production seems an unlikely mechanism for increasing death in these patients. We interpret the lower Glasgow coma score and cerebrospinal fluid glucose concentration on admission in the underweight patients to reflect a reduced capacity to fight against bacterial meningitis in its 124 | www.pidj.com initial stages. Another potential explanation is that their disease had actually lasted longer, although their parents did not report it, because severely malnourished patients have silent infections.8 The slower capillary filling time reflects systemic compromise, sometimes septicemia, associated with death in the underweight patients.20 Prompt recognition of underweight in a patient with meningitis is important, because, especially if severe, it should and can be treated. The recommended care consists of frequent feedings day and night, correction of electrolyte and micronutrient imbalances and, if there is a need for rehydration, use of low-sodium fluids with close monitoring for signs of fluid overload.21 The effect of this approach has been proven to reduce fatality rates in 2 resource-poor South African hospitals.20,22 Because we did not register potential edema, there is a possibility that some patients with kwashiorkor were falsely classified as normal or as less underweight than they truly were. Kwashiorkor is infrequent in the participating centers, but we lack exact data of its prevalence. Also, we did not have the data for the better nutritional status index, the weight-for-height measurement. These limitations should be kept in mind when interpreting the results, but we do not believe that they substantially blurred the message of our study. The strengths of our study are its great number of patients, the complete range of nutritional conditions, and the prospectively collected data. This permitted a separate analysis of the different stages of malnutrition and of the different outcomes, and meaningful results also from the multivariate analysis. We were left with 2 major lessons: First, when evaluating different treatments for bacterial meningitis, the nutritional status, besides the presenting status,14 is a pivotal cofactor to be taken into account. Second, while awaiting large-scale vaccinations against bacterial meningitis also in the poor world, the community treatment of malnutrition should be prioritized and its hospital management21 added to the treatment of bacterial meningitis in the underweight patient. ACKNOWLEDGMENTS The authors thank Dr. Ralf Clemens, then with GlaxoSmithKline, in helping to get the study started. The LatAm Bacterial Meningitis Study comprised the following people and institutions: Josefina Fernández, Clinica Infantil Dr. Robert Reid Cabral, Santo Domingo, Dominican Republic; Antonio Gonzalez Mata, Hospital Pediatrico Dr. Augustin Zubillaga, Barquisimeto, Venezuela; Inés Zavala, Hospital de de Niños Dr. Roberto Gilbert, Guayaquil, Ecuador; Antonio Arbo, Instituto de Medicina Tropical, Universidad Nacional de Asunción, Asunción, Paraguay; Silvia Gonzalez Ayala, Hospital de Niños Sor María Ludovica, La Plata, Argentina; Rosa Bologna, Hospital de Pediatría Dr. Juan P. Garrahan, Buenos Aires, Argentina; Greta Miño, Hospital del Niño Dr. Francisco de Icaza Bustamante, Guayaquil, Ecuador; José Goyo Rivas, Hospital Universitario de los Andes, Mérida, Venezuela; Eduardo López, Hospital de Niños Dr. Ricardo Gutiérrez, Buenos Aires, Argentina. REFERENCES 1. Tsai CJ, Griffin MR, Nuorti JP, et al. 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Geneva, Switzerland: WHO; 2000. 22. Bhutta ZA, Ahmed T, Black RE, et al. What works? Interventions for maternal and child undernutrition and survival. Lancet. 2008;371:417– 440. www.pidj.com | 125