Acta Clinica Belgica International Journal of Clinical and Laboratory Medicine
ISSN: 1784-3286 (Print) 2295-3337 (Online) Journal homepage: http://www.tandfonline.com/loi/yacb20
Haemophilus influenzae: a forgotten cause of neonatal sepsis? A. Dobbelaere, P. Jeannin, T. Bovyn & L. Ide To cite this article: A. Dobbelaere, P. Jeannin, T. Bovyn & L. Ide (2015) Haemophilus influenzae: a forgotten cause of neonatal sepsis?, Acta Clinica Belgica, 70:3, 204-206, DOI: 10.1179/2295333714Y.0000000104 To link to this article: http://dx.doi.org/10.1179/2295333714Y.0000000104
Published online: 02 Dec 2014.
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Date: 05 April 2016, At: 01:10
Case Report
Haemophilus influenzae: a forgotten cause of neonatal sepsis? A. Dobbelaere1, P. Jeannin2, T. Bovyn3, L. Ide4 1
UZ Gent, Gent, Belgium, 2Department of Pediatrics, Jan Palfijn ziekenhuis Gent, Gent, Belgium, 3Department of Obstetrics & Gynaecology, Jan Palfijn ziekenhuis Gent, Gent, Belgium, 4Department of Microbiology & Infection Control, Jan Palfijn ziekenhuis Gent, Gent, Belgium
Downloaded by [Texas A & M International University] at 01:10 05 April 2016
Due to the introduction of the conjugate vaccine against serotype b, neonatal sepsis caused by Haemophilus influenzae became very rare. There is little data in Belgium concerning the prevalence of H. influenzae early onset neonatal sepsis and articles about neonatal sepsis and H. influenzae published in the last decade are scarce. We report two invasive infections with a non-typeable H. influenzae. These cases show that neonatal sepsis caused by non-typeable H. influenzae may be underestimated and we believe that there is need for a better registration of this kind of infection. Keywords: Haemophilus influenzae, Early-onset neonatal sepsis, Mors in utero, Non-typeable Haemophilus influenzae
Introduction Neonatal sepsis is well-known for its important morbidity and mortality.1 Neonatal sepsis is categorized in two groups: early-onset (EONS) and lateonset (infection during the first three days of life and between four and ninety days of life, respectively). EONS mostly results from vertical transmission intrapartum.2 Haemophilus influenzae is an extremely rare cause of EONS.3 H. influenzae is subdivided into serotypes (a–f) on the basis of its polysaccharide capsule. Most of the strains have no capsule and are defined as nontypeable Haemophilus influenzae (NTHi).4 The encapsulated strains are well-known to be associated with invasive disease. Type b is particularly known to be the most virulent strain, but both encapsulated strains and NTHi can cause EONS.5 The bacterium is also subdivided into eight biotypes (I–VIII) on the basis of differences in biochemical reactions.6 Some studies have shown an association between certain biotypes and serotypes, the anatomical location of the bacterium and the possibility of infection. However, those associations are rather weak and inconsistent.7 From 1988, the childhood conjugate vaccine against H. influenzae type b (Hib) was introduced in most developed countries. As a result, infection with the serotype b nearly disappeared in these countries. Therefore, the percentage of EONS caused by H. influenzae decreased remarkably. Although the inciCorrespondence to: Dr L. Ide, Department of Microbiology & Infection Control, Jan Palfijn ziekenhuis Gent, H. Dunantlaan 5, 9000 Gent, Belgium. Email: [email protected]
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ß Acta Clinica Belgica 2015 DOI 10.1179/2295333714Y.0000000104
dence of NTHi EONS remained stable,3 it became relatively more important because of the decrease in Hib EONS.8 Especially preterm infants are at risk for NTHi EONS.3
Case Report 1 A 26-year-old pregnant Caucasian woman (gravida 1, para 0) was admitted to the department of obstetrics with fever (38.6uC). Blood results revealed an elevated C-reactive protein (CRP) of 50.0 mg/l (normal range, 0.0–5.0 mg/l), as well as a leucocytosis of 18 240 leukocytes/ml (normal range, 4000–11 000/ ml). In order to prevent foetal complications, labour was induced at 35 weeks of gestation. Intrapartum empiric antibiotics (ampicillin) were administrated as the patient was Group B streptococcus (GBS) positive. After half an hour of uncomplicated labour, the baby was born. The amniotic fluid was clear. An Apgar score of 4 and 8 was given after 1 and 5 minutes, respectively. The baby was hypotonic and showed respiratory distress. Because of the respiratory distress, acidosis and prematurity, the baby was transferred to the neonatal care unit, where oxygen therapy was started. Blood cultures were collected and empiric antibiotic treatment with intravenous benzylpenicillin 100.000 IE every 12 hours and tobramycin (ObracinH) 8 mg every 4 hours was administrated. A postpartum CRP of 26 mg/l, hypovolemia and hypoglycaemia were consistent with the diagnosis of sepsis. The second day postpartum, the baby was slightly more alert. Laboured breathing and moaning disappeared. The acidosis was normalizing but CRP continued to
Acta Clinica Belgica
2015
VOL.
70
NO.
3
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Dobbelaere et al.
increase up to 70.3 mg/l. Chest X-ray showed bilateral ground glass opacities. Urine sediment was normal and urine culture was negative. Blood cultures yielded H. influenzae. The strain was ampicillin resistant, but amoxicillin-clavulanate, ceftriaxone, levofloxacin and co-trimoxazol susceptible. The strain was sent to the national reference centre for H. influenzae (UMC, StPierre, Brussels, Belgium) and characterized as NTHi, biotype II. The same strain was also found in the placenta and in the eye of the newborn. Ampicillin was not susceptible and therefore antibiotic therapy was changed on the third day to a combination of cefotaxime (ClaforanH) 26110 mg/day with tobramycin (ObracinH). CRP eventually decreased to 46.1 mg/ l. The baby improved and the inflammatory parameters normalized from the fourth day on.
Case Report 2 A 30-year-old pregnant Caucasian woman (gravida 4, para 2, abortus 1) was admitted with preterm premature rupture of the membranes. She was GBS negative. She had no fever. At arrival the uterus was already contractile. Blood tests revealed a CRP of 28.4 mg/l without leucocytosis (10 180 leukocytes/ ml). Foetal death was diagnosed at 18 weeks and 4 days performing an abdominal ultrasound and cardiotocography. The foetus showed no congenital anomalies. Histological examination of the placenta showed an acute purulent chorioamnionitis and fusinitis suggestive of an ascending infection. H. influenzae was cultured in the umbilical cord. The strain was ampicillin, amoxicillin-clavulanate, ceftriaxone, levofloxacin and co-trimoxazol susceptible. The strain was characterized as NTHi, biotype V by the national reference centre for H. influenzae.
Discussion The incidence of EONS has decreased remarkably in the last decades to 0.5–1.2 cases per thousand live births,9 but it still remains one of the leading causes of neonatal mortality. GBS and to a smaller extent Escherichia coli are by far the most common causative pathogens of EONS.2 Trends in the epidemiology of EONS show a decreasing incidence of GBS disease due to the implementation of GBS screening programs and treatment.10 In the first case benzylpenicillin and tobramycin were started empirically targeting the highly pathogenic bacteria E. coli and GBS.11 Once H. influenzae with beta-lactamase activity was cultured, therapy was switched to cefotaxim and tobramycin, although tobramycin is sensu stricto not necessary. On the other hand, in this particular situation cefotaxim is the therapy of choice because its ability to cross the blood brain barrier. The portion of EONS caused by H. influenzae is very small. According to Stoll et al. only 3% of all
Haemophilus influenzae
pathogens associated with EONS can be attributed to Haemophilus sp.10 A portion of 3.4% of H. influenzae as a causative organism of EONS was reported by Cohen-Wolkowiez et al.1 A similar percentage of 3.3– 4.9% was reported by Sgro et al.12 In our two cases the strains were not encapsulated. The majority of neonatal H. influenzae infections are caused by the NTHi strains.13 H. influenzae is a typical human pathogen. It is a non-motile, gram-negative coccobacillus that requires special growth factors: hemin (factor X) and nicotinamide adenine dinucleotide (NAD or factor V). It is quite easy to make the diagnose in the routine microbiology laboratory. With its decrease in infection since the introduction of the conjugate vaccine, H. influenzae has been ignored as an important pathogen. Articles about neonatal sepsis and H. influenzae published in the last decade are scarce. When we searched the Pubmed database for articles with the following query: ‘Haemophilus influenzae (MeSH Terms) and neonatal (All Fields) and sepsis (All Fields)’ only 47 results were found. Only five of the 47 articles were published after the year 2000. The majority of the articles were published in the early nineties. In this period, the beneficial results of the recently introduced conjugate Hib vaccine were published. Therefore we propose a registration of this kind of infections to see whether if H. influenzae EONS is re-emerging or not.
Conclusion H. influenzae (early onset) neonatal sepsis is very rare. Since the introduction of the Hib vaccine, neonatal H. influenzae infections are most likely NTHi strains. Although less invasive, NTHi should be recognized as an important foetal and neonatal pathogen. There is little data in Belgium concerning the prevalence of H. influenzae EONS. The number of cases in Belgium might be underestimated as there is no unique straightforward registration system. Introduction of such a registration would be helpful to investigate if H. influenzae is a re-emerging pathogen.
Acknowledgements The authors thank Tine Grammens (WIV) and Steven Vervaeke (AZ Delta) for their advice.
References 1 Cohen-Wolkowiez M, Moran C, Benjamin DK, Cotten CM, Clark RH, Smith PB, et al. Early and late onset sepsis in late preterm infants. Pediatr Infect Dis J. 2009;5:1052–6. 2 Shah BA, Padbury JF. Neonatal sepsis: An old problem with new insights. Virulence. 2014;5:170–8. 3 Agrawal A, Murphy TF. Haemophilus influenzae infections in the H. influenzae type b conjugate vaccine era. J Clin Microbiol. 2011;14:3728–32. 4 O’Neill JM, St GJ III, Cutter D, Adderson EE, Anyanwu J, Jacobs RF, et al. Invasive disease due to nontypeable Haemophilus influenzae among children in Arkansas. J Clin Microbiol. 2003;41:3064–9.
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5 Rusin P, Adam RD, Peterson EA, Ryan KJ, Sinclair NA, Weinstein L. Haemophilus influenzae: an important cause of maternal and neonatal infections. Obstet Gynecol. 1991;77(1):92–6. 6 Sottnek FO, Albritton WL. Haemophilus influenza biotype VIII. J Clin Microbiol. 1984;20:815–6. 7 Warren S, Tristram S, Bradbury RS. Maternal and neonatal sepsis caused by Haemophilus influenzae type d. J Med Microbiol. 2010;59:370–2. 8 Livorsi DJ, MacNeil JR, Cohn AC, Bareta J, Zansky S, Petit S, et al. Invasive Haemophilus influenzae in the United States, 1999–2008: epidemiology and outcomes. J Infect. 2012;65:496–504. 9 Escobar GJ, Puopolo KM, Wi S, Turk BJ, Kuzniewicz MW, Walsh EM, et al. Stratification of risk of early-onset sepsis in newborn§ 34 weeks’ gestation. Pediatrics. 2014;133(1):30–6.
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10 Stoll BJ, Hansen NI, Sa´nchez PJ, Faix RG, Poindexter BB, Van Meurs KP, et al. Early onset neonatal sepsis: the burden of group B Streptococcal and E. coli disease continues. Pediatrics. 2011;127:817–26. 11 Mahieu L, Langhendries JP, Cossey V, De Praeter C, Lepage P, Melin P. Management of the neonate at risk for early-onset Group B streptococcal disease (GBS EOD): new paediatric guidelines in Belgium. Acta Clin Belg. 2014;69(5):313–9. 12 Sgro M, Shah PS, Campbell D, Tenuta A, Shivananda S, Lee SK. Early-onset neonatal sepsis: rate and organism pattern between 2003 and 2008. J Perinatol. 2011;31(12):794–8. 13 Ladhani S, Slack MP, Heath PT, von Gottberg A, Chandra M, Ramsay ME. Invasive Haemophilus influenzae disease, Europe, 1996–2006. Emerg Infect Dis. 2010;16:455–63.
ISSN: 1784-3286 (Print) 2295-3337 (Online) Journal homepage: http://www.tandfonline.com/loi/yacb20
Haemophilus influenzae: a forgotten cause of neonatal sepsis? A. Dobbelaere, P. Jeannin, T. Bovyn & L. Ide To cite this article: A. Dobbelaere, P. Jeannin, T. Bovyn & L. Ide (2015) Haemophilus influenzae: a forgotten cause of neonatal sepsis?, Acta Clinica Belgica, 70:3, 204-206, DOI: 10.1179/2295333714Y.0000000104 To link to this article: http://dx.doi.org/10.1179/2295333714Y.0000000104
Published online: 02 Dec 2014.
Submit your article to this journal
Article views: 35
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=yacb20 Download by: [Texas A & M International University]
Date: 05 April 2016, At: 01:10
Case Report
Haemophilus influenzae: a forgotten cause of neonatal sepsis? A. Dobbelaere1, P. Jeannin2, T. Bovyn3, L. Ide4 1
UZ Gent, Gent, Belgium, 2Department of Pediatrics, Jan Palfijn ziekenhuis Gent, Gent, Belgium, 3Department of Obstetrics & Gynaecology, Jan Palfijn ziekenhuis Gent, Gent, Belgium, 4Department of Microbiology & Infection Control, Jan Palfijn ziekenhuis Gent, Gent, Belgium
Downloaded by [Texas A & M International University] at 01:10 05 April 2016
Due to the introduction of the conjugate vaccine against serotype b, neonatal sepsis caused by Haemophilus influenzae became very rare. There is little data in Belgium concerning the prevalence of H. influenzae early onset neonatal sepsis and articles about neonatal sepsis and H. influenzae published in the last decade are scarce. We report two invasive infections with a non-typeable H. influenzae. These cases show that neonatal sepsis caused by non-typeable H. influenzae may be underestimated and we believe that there is need for a better registration of this kind of infection. Keywords: Haemophilus influenzae, Early-onset neonatal sepsis, Mors in utero, Non-typeable Haemophilus influenzae
Introduction Neonatal sepsis is well-known for its important morbidity and mortality.1 Neonatal sepsis is categorized in two groups: early-onset (EONS) and lateonset (infection during the first three days of life and between four and ninety days of life, respectively). EONS mostly results from vertical transmission intrapartum.2 Haemophilus influenzae is an extremely rare cause of EONS.3 H. influenzae is subdivided into serotypes (a–f) on the basis of its polysaccharide capsule. Most of the strains have no capsule and are defined as nontypeable Haemophilus influenzae (NTHi).4 The encapsulated strains are well-known to be associated with invasive disease. Type b is particularly known to be the most virulent strain, but both encapsulated strains and NTHi can cause EONS.5 The bacterium is also subdivided into eight biotypes (I–VIII) on the basis of differences in biochemical reactions.6 Some studies have shown an association between certain biotypes and serotypes, the anatomical location of the bacterium and the possibility of infection. However, those associations are rather weak and inconsistent.7 From 1988, the childhood conjugate vaccine against H. influenzae type b (Hib) was introduced in most developed countries. As a result, infection with the serotype b nearly disappeared in these countries. Therefore, the percentage of EONS caused by H. influenzae decreased remarkably. Although the inciCorrespondence to: Dr L. Ide, Department of Microbiology & Infection Control, Jan Palfijn ziekenhuis Gent, H. Dunantlaan 5, 9000 Gent, Belgium. Email: [email protected]
204
ß Acta Clinica Belgica 2015 DOI 10.1179/2295333714Y.0000000104
dence of NTHi EONS remained stable,3 it became relatively more important because of the decrease in Hib EONS.8 Especially preterm infants are at risk for NTHi EONS.3
Case Report 1 A 26-year-old pregnant Caucasian woman (gravida 1, para 0) was admitted to the department of obstetrics with fever (38.6uC). Blood results revealed an elevated C-reactive protein (CRP) of 50.0 mg/l (normal range, 0.0–5.0 mg/l), as well as a leucocytosis of 18 240 leukocytes/ml (normal range, 4000–11 000/ ml). In order to prevent foetal complications, labour was induced at 35 weeks of gestation. Intrapartum empiric antibiotics (ampicillin) were administrated as the patient was Group B streptococcus (GBS) positive. After half an hour of uncomplicated labour, the baby was born. The amniotic fluid was clear. An Apgar score of 4 and 8 was given after 1 and 5 minutes, respectively. The baby was hypotonic and showed respiratory distress. Because of the respiratory distress, acidosis and prematurity, the baby was transferred to the neonatal care unit, where oxygen therapy was started. Blood cultures were collected and empiric antibiotic treatment with intravenous benzylpenicillin 100.000 IE every 12 hours and tobramycin (ObracinH) 8 mg every 4 hours was administrated. A postpartum CRP of 26 mg/l, hypovolemia and hypoglycaemia were consistent with the diagnosis of sepsis. The second day postpartum, the baby was slightly more alert. Laboured breathing and moaning disappeared. The acidosis was normalizing but CRP continued to
Acta Clinica Belgica
2015
VOL.
70
NO.
3
Downloaded by [Texas A & M International University] at 01:10 05 April 2016
Dobbelaere et al.
increase up to 70.3 mg/l. Chest X-ray showed bilateral ground glass opacities. Urine sediment was normal and urine culture was negative. Blood cultures yielded H. influenzae. The strain was ampicillin resistant, but amoxicillin-clavulanate, ceftriaxone, levofloxacin and co-trimoxazol susceptible. The strain was sent to the national reference centre for H. influenzae (UMC, StPierre, Brussels, Belgium) and characterized as NTHi, biotype II. The same strain was also found in the placenta and in the eye of the newborn. Ampicillin was not susceptible and therefore antibiotic therapy was changed on the third day to a combination of cefotaxime (ClaforanH) 26110 mg/day with tobramycin (ObracinH). CRP eventually decreased to 46.1 mg/ l. The baby improved and the inflammatory parameters normalized from the fourth day on.
Case Report 2 A 30-year-old pregnant Caucasian woman (gravida 4, para 2, abortus 1) was admitted with preterm premature rupture of the membranes. She was GBS negative. She had no fever. At arrival the uterus was already contractile. Blood tests revealed a CRP of 28.4 mg/l without leucocytosis (10 180 leukocytes/ ml). Foetal death was diagnosed at 18 weeks and 4 days performing an abdominal ultrasound and cardiotocography. The foetus showed no congenital anomalies. Histological examination of the placenta showed an acute purulent chorioamnionitis and fusinitis suggestive of an ascending infection. H. influenzae was cultured in the umbilical cord. The strain was ampicillin, amoxicillin-clavulanate, ceftriaxone, levofloxacin and co-trimoxazol susceptible. The strain was characterized as NTHi, biotype V by the national reference centre for H. influenzae.
Discussion The incidence of EONS has decreased remarkably in the last decades to 0.5–1.2 cases per thousand live births,9 but it still remains one of the leading causes of neonatal mortality. GBS and to a smaller extent Escherichia coli are by far the most common causative pathogens of EONS.2 Trends in the epidemiology of EONS show a decreasing incidence of GBS disease due to the implementation of GBS screening programs and treatment.10 In the first case benzylpenicillin and tobramycin were started empirically targeting the highly pathogenic bacteria E. coli and GBS.11 Once H. influenzae with beta-lactamase activity was cultured, therapy was switched to cefotaxim and tobramycin, although tobramycin is sensu stricto not necessary. On the other hand, in this particular situation cefotaxim is the therapy of choice because its ability to cross the blood brain barrier. The portion of EONS caused by H. influenzae is very small. According to Stoll et al. only 3% of all
Haemophilus influenzae
pathogens associated with EONS can be attributed to Haemophilus sp.10 A portion of 3.4% of H. influenzae as a causative organism of EONS was reported by Cohen-Wolkowiez et al.1 A similar percentage of 3.3– 4.9% was reported by Sgro et al.12 In our two cases the strains were not encapsulated. The majority of neonatal H. influenzae infections are caused by the NTHi strains.13 H. influenzae is a typical human pathogen. It is a non-motile, gram-negative coccobacillus that requires special growth factors: hemin (factor X) and nicotinamide adenine dinucleotide (NAD or factor V). It is quite easy to make the diagnose in the routine microbiology laboratory. With its decrease in infection since the introduction of the conjugate vaccine, H. influenzae has been ignored as an important pathogen. Articles about neonatal sepsis and H. influenzae published in the last decade are scarce. When we searched the Pubmed database for articles with the following query: ‘Haemophilus influenzae (MeSH Terms) and neonatal (All Fields) and sepsis (All Fields)’ only 47 results were found. Only five of the 47 articles were published after the year 2000. The majority of the articles were published in the early nineties. In this period, the beneficial results of the recently introduced conjugate Hib vaccine were published. Therefore we propose a registration of this kind of infections to see whether if H. influenzae EONS is re-emerging or not.
Conclusion H. influenzae (early onset) neonatal sepsis is very rare. Since the introduction of the Hib vaccine, neonatal H. influenzae infections are most likely NTHi strains. Although less invasive, NTHi should be recognized as an important foetal and neonatal pathogen. There is little data in Belgium concerning the prevalence of H. influenzae EONS. The number of cases in Belgium might be underestimated as there is no unique straightforward registration system. Introduction of such a registration would be helpful to investigate if H. influenzae is a re-emerging pathogen.
Acknowledgements The authors thank Tine Grammens (WIV) and Steven Vervaeke (AZ Delta) for their advice.
References 1 Cohen-Wolkowiez M, Moran C, Benjamin DK, Cotten CM, Clark RH, Smith PB, et al. Early and late onset sepsis in late preterm infants. Pediatr Infect Dis J. 2009;5:1052–6. 2 Shah BA, Padbury JF. Neonatal sepsis: An old problem with new insights. Virulence. 2014;5:170–8. 3 Agrawal A, Murphy TF. Haemophilus influenzae infections in the H. influenzae type b conjugate vaccine era. J Clin Microbiol. 2011;14:3728–32. 4 O’Neill JM, St GJ III, Cutter D, Adderson EE, Anyanwu J, Jacobs RF, et al. Invasive disease due to nontypeable Haemophilus influenzae among children in Arkansas. J Clin Microbiol. 2003;41:3064–9.
Acta Clinica Belgica
2015
VOL .
70
NO .
3
205
Dobbelaere et al.
Haemophilus influenzae
Downloaded by [Texas A & M International University] at 01:10 05 April 2016
5 Rusin P, Adam RD, Peterson EA, Ryan KJ, Sinclair NA, Weinstein L. Haemophilus influenzae: an important cause of maternal and neonatal infections. Obstet Gynecol. 1991;77(1):92–6. 6 Sottnek FO, Albritton WL. Haemophilus influenza biotype VIII. J Clin Microbiol. 1984;20:815–6. 7 Warren S, Tristram S, Bradbury RS. Maternal and neonatal sepsis caused by Haemophilus influenzae type d. J Med Microbiol. 2010;59:370–2. 8 Livorsi DJ, MacNeil JR, Cohn AC, Bareta J, Zansky S, Petit S, et al. Invasive Haemophilus influenzae in the United States, 1999–2008: epidemiology and outcomes. J Infect. 2012;65:496–504. 9 Escobar GJ, Puopolo KM, Wi S, Turk BJ, Kuzniewicz MW, Walsh EM, et al. Stratification of risk of early-onset sepsis in newborn§ 34 weeks’ gestation. Pediatrics. 2014;133(1):30–6.
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10 Stoll BJ, Hansen NI, Sa´nchez PJ, Faix RG, Poindexter BB, Van Meurs KP, et al. Early onset neonatal sepsis: the burden of group B Streptococcal and E. coli disease continues. Pediatrics. 2011;127:817–26. 11 Mahieu L, Langhendries JP, Cossey V, De Praeter C, Lepage P, Melin P. Management of the neonate at risk for early-onset Group B streptococcal disease (GBS EOD): new paediatric guidelines in Belgium. Acta Clin Belg. 2014;69(5):313–9. 12 Sgro M, Shah PS, Campbell D, Tenuta A, Shivananda S, Lee SK. Early-onset neonatal sepsis: rate and organism pattern between 2003 and 2008. J Perinatol. 2011;31(12):794–8. 13 Ladhani S, Slack MP, Heath PT, von Gottberg A, Chandra M, Ramsay ME. Invasive Haemophilus influenzae disease, Europe, 1996–2006. Emerg Infect Dis. 2010;16:455–63.
