Download Influence of Malnutrition on the Course of Childhood

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
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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
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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
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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. Changing epidemiology of pneumococcal meningitis after the introduction of pneumococcal conjugate vaccine
in the United States. Clin Infect Dis. 2008;46:1664 –1672.
2. Molyneux E, Riordan FA, Walsh A. Acute bacterial meningitis in children
presenting to the Royal Liverpool Children’s Hospital, Liverpool, UK and
the Queen Elizabeth Central Hospital in Blantyre, Malawi: a world of
difference. Ann Trop Paediatr. 2006;26:29 –37.
3. Katona P, Katona-Apte J. The interaction between nutrition and infection.
Clin Infect Dis. 2008;46:1582–1588.
4. Hailemeskel H, Tafari N. Bacterial meningitis in childhood in an African
city: factors influencing aetiology and outcome. Acta Paediatr Scand.
1978;67:725–730.
© 2010 Lippincott Williams & Wilkins
The Pediatric Infectious Disease Journal • Volume 29, Number 2, February 2010
5. Hemalatha R, Bhaskaram P, Balakrishna N, et al. Association of tumour
necrosis factor alpha and malnutrition with outcome in children with acute
bacterial meningitis. Indian J Med Res. 2002;115:55–58.
6. Pelkonen T, Roine I, Monteiro L, et al. Risk factors for death and severe
neurological sequelae in childhood bacterial meningitis in sub-Saharan
Africa. Clin Infect Dis. 2009;48:1107–1110.
7. de Onis M, Blössner M. The WHO global database on child growth and malnutrition: methodology and applications. Int J Epidemiol. 2003;32:518–526.
8. Cunningham-Rundles S, McNeeley DF, Moon A. Mechanisms of nutrient
modulation of the immune response. J Allergy Clin Immunol. 2005;115:
1119 –1128.
9. Kanasky WF Jr, Anton SD, Rodrigue JR, et al. Impact of body weight on
long-term survival after lung transplantation. Chest. 2002;121:401– 406.
10. Peltola H, Roine I, Fernandez J, et al. Adjuvant glycerol and/or dexamethasone to improve the outcomes of childhood bacterial meningitis: a prospective, randomized, double-blind, placebo-controlled trial. Clin Infect
Dis. 2007;45:1277–1286.
11. Roine I, Saukkoriipi A, Leinonen M; LatAm Meningitis Study Group.
Microbial genome count in cerebrospinal fluid compared with clinical
characteristics in pneumococcal and Haemophilus influenzae type b meningitis in children. Diagn Microbiol Infect Dis. 2009;63:16 –23.
12. Z-score. Available at: http://en.wiktionary.org/wiki/Z_score. Assessed
April 13, 2009.
13. WHO Anthro 2005, Beta version February 17, 2006: software for assessing
growth and development of the world’s children. Geneva: WHO, 2006.
Available at: http://www.who.int/childgrowth/software/en/. Assessed January 6, 2009.
© 2010 Lippincott Williams & Wilkins
Malnutrition in Meningitis
14. Roine I, Peltola H, Fernandez J, et al. Influence of admission findings on
death and neurological outcome from childhood bacterial meningitis. Clin
Infect Dis. 2008;46:1248 –1252.
15. The international development center. Module 26: Dealing with confounding variables. Available at: http://www.idrc.ca/en/ev-56459 –201–1-DO_
TOPIC.html. Assessed April 13, 2009.
16. Caulfield LE, de Onis M, Blössner M, et al. Undernutrition as an underlying
cause of child deaths associated with diarrhea, pneumonia, malaria, and
measles. Am J Clin Nutr. 2004;80:193–198.
17. Pelletier D, Frongillo EA, Schroeder DG, et al. The effects of malnutrition
on child mortality in developing countries. Bull World Health Organ.
1995;73:443– 448.
18. Palacio A, Lopez M, Perez-Bravo F, et al. Leptin levels are associated with
immune response in malnourished infants. J Clin Endocrinol Metab. 2002;
87:3040 –3046.
19. Nau R, Brück W. Neuronal injury in bacterial meningitis: mechanisms and
implications for therapy. Trends Neurosci. 2002;25:38 – 45.
20. Ashworth A, Chopra M, McCoy D, et al. WHO guidelines for management of severe malnutrition in rural South African hospitals: effect on
case fatality and the influence of operational factors. Lancet. 2004;363:
1110 –1115.
21. WHO. Management of the Child with a Serious Infection or Malnutrition.
Guidelines for Care at the First-Referral Level in Developing Countries.
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.
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