ESPID Reports and Reviews CONTENTS Performance of Adjunctive Therapy in Bacterial Meningitis
EDITORIAL BOARD Co-Editors: Delane Shingadia and Irja Lutsar Board Members David Burgner (Melbourne, Australia) Luisa Galli (Rome, Italy) Christiana Nascimento-Carvalho (Bahia, Brazil) Ville Peltola (Turku, Finland)
Nicol Ritz (Basel, Switzerland) Ira Shah (Mumbai, India) Matthew Snape (Oxford, UK) George Syrogiannopoulos (Larissa, Greece)
Tobias Tenenbaum (Mannhein, Germany) Marc Terbruegge (Southampton, UK) Marceline van Furth (Amsterdam, The Netherlands) Anne Vergison (Brussels, Belgium)
Performance of Adjunctive Therapy in Bacterial Meningitis Depends on Circumstances Heikki Peltola, MD* and Stephen L. Leib, MD†
U
nlike in most of the industrialized countries where the grip of bacterial meningitis (BM) of childhood has much loosened thanks to the large-scale Haemophilus influenzae type b (Hib) and Streptococcus pneumoniae (and Neisseria meningitidis group A in the meningitis belt of Africa) vaccinations, the global toll continues to be substantial. Reliable numbers are lacking, but estimated one million cases annually are hardly far from reality. Most cases are encountered in poor countries where mortality exceeds 30% and every second survivor is left with permanent sequelae. In a resource-poor setting, a deaf or otherwise neurofunctionally impaired child is a tragedy. As newer antibiotics alone have not improved the prognosis, one has tried several “adjuvant” therapies. While dexamethasone (DXM) and, to a lesser extent, glycerol (GLY) have been studied among patients, some other promising approaches, such as the use of nonlytic antibiotics, are so far been tested in animal models.
DEXAMETHASONE DXM has clear positive biochemical effects1 if administered prior to or with the From the *University of Helsinki, and Children’s Hospital, Helsinki University Central Hospital, Helsinki, Finland; and †Institute for Infectious Diseases, University of Bern, and Biology Division, Spiez Laboratory, Spiez, Switzerland. The authors have no funding or conflicts of interest to disclose. Address for correspondence: Heikki Peltola, MD, Välskärinkatu 5 A 13, 00260 Helsinki, Finland. E-mail: [email protected]. Copyright © 2013 by Lippincott Williams & Wilkins ISSN: 0891-3668/13/3212-1381 DOI: 10.1097/INF.0000000000000066
first antibiotic dose, but somewhat surprisingly, no pediatric study, in which the antibiotic has been optimal (third-generation cephalosporin) and different outcomes have been kept separated, has met statistical significance even in Hib meningitis with perfect timing of DXM.2,3 Keeping outcomes separated is important because the pathogenesis differs. A shortcoming common to all earlier DXM studies is the sample size too small to show anything, positive or negative results. A pivotal early and much-cited study of Lebel et al.4 comprises 2 sets of children of whom 100 were treated with cefuroxime and 100 with ceftriaxone. Meager audiological benefit was found in the first but not second group. To get a better picture of the entirety, 10 meta-analyses since 1989 have examined DXM in BM.3 One would expect all this information to have answered the burning question—Does DXM help the child with meningitis or not? So far it has not been answered conclusively. After combining 8 series from Western countries, one meta-analysis5 reached a significant reduction of hearing loss in Hib meningitis (N varied from 28 to 82)—odds ratio 0.31 (95% confidence interval: 0.14–0.69)—but when individual patient data of 833 children from Latin America and Malawi were scrutinized,2 no effect was found. Another meta-analysis6 reached significant reduction in mortality only after including a quasirandomized study from Egypt.7 A major heterogeneity of the data sources blurs a balanced interpretation. Even more confusing is the fact that all meta-analyses, including the Cochrane review,8 have ignored the single most important covariate predicting death or neurological sequelae, the patient’s presenting condition.9 Of importance, it overrides even the
The Pediatric Infectious Disease Journal • Volume 32, Number 12, December 2013
role of etiology per se.9 In Latin America,
EDITORIAL BOARD Co-Editors: Delane Shingadia and Irja Lutsar Board Members David Burgner (Melbourne, Australia) Luisa Galli (Rome, Italy) Christiana Nascimento-Carvalho (Bahia, Brazil) Ville Peltola (Turku, Finland)
Nicol Ritz (Basel, Switzerland) Ira Shah (Mumbai, India) Matthew Snape (Oxford, UK) George Syrogiannopoulos (Larissa, Greece)
Tobias Tenenbaum (Mannhein, Germany) Marc Terbruegge (Southampton, UK) Marceline van Furth (Amsterdam, The Netherlands) Anne Vergison (Brussels, Belgium)
Performance of Adjunctive Therapy in Bacterial Meningitis Depends on Circumstances Heikki Peltola, MD* and Stephen L. Leib, MD†
U
nlike in most of the industrialized countries where the grip of bacterial meningitis (BM) of childhood has much loosened thanks to the large-scale Haemophilus influenzae type b (Hib) and Streptococcus pneumoniae (and Neisseria meningitidis group A in the meningitis belt of Africa) vaccinations, the global toll continues to be substantial. Reliable numbers are lacking, but estimated one million cases annually are hardly far from reality. Most cases are encountered in poor countries where mortality exceeds 30% and every second survivor is left with permanent sequelae. In a resource-poor setting, a deaf or otherwise neurofunctionally impaired child is a tragedy. As newer antibiotics alone have not improved the prognosis, one has tried several “adjuvant” therapies. While dexamethasone (DXM) and, to a lesser extent, glycerol (GLY) have been studied among patients, some other promising approaches, such as the use of nonlytic antibiotics, are so far been tested in animal models.
DEXAMETHASONE DXM has clear positive biochemical effects1 if administered prior to or with the From the *University of Helsinki, and Children’s Hospital, Helsinki University Central Hospital, Helsinki, Finland; and †Institute for Infectious Diseases, University of Bern, and Biology Division, Spiez Laboratory, Spiez, Switzerland. The authors have no funding or conflicts of interest to disclose. Address for correspondence: Heikki Peltola, MD, Välskärinkatu 5 A 13, 00260 Helsinki, Finland. E-mail: [email protected]. Copyright © 2013 by Lippincott Williams & Wilkins ISSN: 0891-3668/13/3212-1381 DOI: 10.1097/INF.0000000000000066
first antibiotic dose, but somewhat surprisingly, no pediatric study, in which the antibiotic has been optimal (third-generation cephalosporin) and different outcomes have been kept separated, has met statistical significance even in Hib meningitis with perfect timing of DXM.2,3 Keeping outcomes separated is important because the pathogenesis differs. A shortcoming common to all earlier DXM studies is the sample size too small to show anything, positive or negative results. A pivotal early and much-cited study of Lebel et al.4 comprises 2 sets of children of whom 100 were treated with cefuroxime and 100 with ceftriaxone. Meager audiological benefit was found in the first but not second group. To get a better picture of the entirety, 10 meta-analyses since 1989 have examined DXM in BM.3 One would expect all this information to have answered the burning question—Does DXM help the child with meningitis or not? So far it has not been answered conclusively. After combining 8 series from Western countries, one meta-analysis5 reached a significant reduction of hearing loss in Hib meningitis (N varied from 28 to 82)—odds ratio 0.31 (95% confidence interval: 0.14–0.69)—but when individual patient data of 833 children from Latin America and Malawi were scrutinized,2 no effect was found. Another meta-analysis6 reached significant reduction in mortality only after including a quasirandomized study from Egypt.7 A major heterogeneity of the data sources blurs a balanced interpretation. Even more confusing is the fact that all meta-analyses, including the Cochrane review,8 have ignored the single most important covariate predicting death or neurological sequelae, the patient’s presenting condition.9 Of importance, it overrides even the
The Pediatric Infectious Disease Journal • Volume 32, Number 12, December 2013
role of etiology per se.9 In Latin America,
