We searched Medline (via PubMed) and Web of Science with the following search terms “Haemophilus” AND “influenza”, “aegyptius”, “quentini”, “NTHi”, “haemolyticus”, “typing”, “invasive infections”, “prevalence”, “otitis”, “sinusitis”, “conjunctivitis”, “bronchitis”, “COPD”, “cystic fibrosis”, “antibiotic resistance”, “epidemiology”, “b-lactamase”, “TEM-1”, “ROB-1”, “BLNAR”, “BLNAI”, “BLPACR”. Studies needed to be peer reviewed to be eligible for inclusion. Searches were restricted to studies
ReviewNon-typeable Haemophilus influenzae, an under-recognised pathogen
Introduction
When the Haemophilus influenzae type b (Hib) conjugate vaccine was introduced more than 20 years ago, surveillance recorded the rapid reduction of invasive Hib infections and almost no replacement with non-type b encapsulated H influenzae.1 After this reduction, interest in H influenzae declined, as seen by the fall in the number of peer-reviewed papers on H influenzae from 18·4 per 1000 bacteriological papers in 1991 to seven per 1000 in 2009.2
Non-encapsulated (or non-typeable) H influenzae (NTHi) has never had the high profile of Hib or Streptococcus pneumoniae, although NTHi is a common cause of respiratory tract infections in children and adults. HinMax, a group of clinicians and researchers interested in both Moraxella spp and H influenzae, including NTHi, met in 2008 (with 40 delegates) and 2011 (with 27 delegates) and made 24 presentations on H influenzae, including NTHi (Hays JP, Department of Medical Microbiology and Infectious Diseases, Erasmus MC, Rotterdam, The Netherlands, personal communication). At the European Congress of Clinical Microbiology and Infectious Diseases in Vienna in 2010, only 11 of around 4000 oral and poster presentations dealt with NTHi. This apparent lack of interest could be because this pathogen is generally thought to cause infection only in predisposed patients and to be easily treated with β-lactam antibiotics.
In this Review, we make the case for heightened surveillance of NTHi because emerging data point to the increasing importance of NTHi as a pathogen in infections of the upper and lower respiratory tract and in invasive disease, and epidemiological evidence shows an increase in the spread of non-β-lactamase dependent resistance to β-lactam antibiotics. In an attempt to raise the profile of NTHi, a website has been established to provide a single repository of knowledge on the pathogenesis, incidence, and treatment of NTHi disease. The European Monitoring Group on Meningococci (EMGM) recently expanded its scope to include H influenzae.
Section snippets
Haemophilus spp
Haemophilus spp are small fastidious Gram-negative coccobacilli that can be speciated by their requirements for X-factor (haemin) or V-factor (nicotinamide adenine dinucleotide), and other phenotypic characteristics. H influenzae requires both X-factor and V-factor. Some strains of H influenzae are encapsulated and can be divided into six serotypes (a–f) on the basis of their capsular polysaccharide.3 NTHi strains cannot be serotyped by conventional type-specific antiserum agglutination. New
NTHi as a cause of non-invasive infections
The global burden of non-invasive infections with NTHi, such as otitis media, sinusitis, conjunctivitis, exacerbations of chronic obstructive pulmonary disease (COPD), and non-bacteraemic pneumonia is very high (table 1). These infections are mucosal and often polymicrobial. Therefore, the role of NTHi in the pathogenesis of these infections could be under-reported. Development of new and sensitive PCR technology will be invaluable in understanding the cause and pathology of these infections,
NTHi as a cause of invasive infections
Before routine vaccination, Hib was the commonest cause of invasive H influenzae disease, occurring predominantly in healthy children younger than 5 years, for whom it was the commonest cause of bacterial meningitis.91 In England and Wales, 90% of invasive H influenzae infections were caused by Hib, 10% by NTHi, and less than 1% by other serotypes; 23% of NTHi infections occurred in children younger than 5 years.92 NTHi incidence varied by age, ranging from 14·9 per 100 000 per year in neonates
Development of resistance in NTHi
β-lactamase production in H influenzae and NTHi is still the dominant resistance mechanism against β-lactams. The prevalence of β-lactamase in NTHi differs widely worldwide. In the past decade, studies have reported percentages of β-lactamase-positive NTHi between 10% and 25% in most regions (South Africa, Europe, USA, Canada, Central America, South America).113, 114, 115, 116, 117, 118 In some regions (Taiwan, Vietnam, Japan, South Korea), β-lactamase-positive NTHi account for up to 55% of
Conclusion
Improved surveillance of H influenzae is needed to follow the trends described in this Review. National reference centres could have an important role by ensuring comprehensive and standardised surveillance of all cases of invasive H influenzae disease; collections of epidemiological data on cases, including demographic details, underlying comorbidities, risk factors, and outcome of the infection; accurate identification of the organism on the basis of molecular typing methods; and recording of
Search strategy and selection criteria
References (153)
- et al.
The impact of vaccines on pneumonia: key lessons from Haemophilus influenzae type b conjugate vaccines
Vaccine
(2008) - et al.
Cross-infection by non-encapsulated Haemophilus influenzae
Lancet
(1990) - et al.
Nosocomial transmission of disease caused by nontypeable strains of Haemophilus influenzae
Am J Med
(1994) - et al.
Pneumococcal capsular polysaccharides conjugated to protein D for prevention of acute otitis media caused by both Streptococcus pneumoniae and non-typable Haemophilus influenzae: a randomised double-blind efficacy study
Lancet
(2006) - et al.
Update on bacterial conjunctivitis in South Florida
Ophthalmology
(2008) Acute conjunctivitis in childhood
Curr Probl Pediatr
(1994)Current issues in the management of acute bacterial sinusitis in children
Int J Pediatr Otorhinolaryngol
(2007)- et al.
Antimicrobial resistance and clinical effectiveness of co-trimoxazole versus amoxycillin for pneumonia among children in Pakistan: randomised controlled trial
Lancet
(1998) - et al.
Population-based study of non-typable Haemophilus influenzae invasive disease in children and neonates
Lancet
(1993) - et al.
Ten years of Hib vaccination in Italy: prevalence of non-encapsulated Haemophilus influenzae among invasive isolates and the possible impact on antibiotic resistance
Vaccine
(2011)
Predominance of nontypeable Haemophilus influenzae in children with otitis media following introduction of a 3+0 pneumococcal conjugate vaccine schedule
Vaccine
Effect of vaccination with pneumococcal capsular polysaccharides conjugated to Haemophilus influenzae-derived protein D on nasopharyngeal carriage of Streptococcus pneumoniae and H. influenzae in children under 2 years of age
Vaccine
Treatment of chronic maxillary sinusitis in children
Int J Pediatr Otorhinolaryngol
Chronic obstructive pulmonary disease: a worldwide problem
Med Clin North Am
Oral immunotherapy with inactivated nontypeable Haemophilus influenzae reduces severity of acute exacerbations in severe COPD
Chest
Evaluation and outcome of young children with chronic cough
Chest
Bacterial bronchitis caused by Streptococcus pneumoniae and nontypable Haemophilus influenzae in children: the impact of vaccination
Chest
Early bacteriologic, immunologic, and clinical courses of young infants with cystic fibrosis identified by neonatal screening
J Pediatr
Haemophilus influenzae in children with cystic fibrosis: antimicrobial susceptibility, molecular epidemiology, distribution of adhesins and biofilm formation
Int J Med Microbiol
Invasive disease caused by Haemophilus influenzae in Sweden 1997–2009; evidence of increasing incidence and clinical burden of non-type b strains
Clin Microbiol Infect
No evidence for Haemophilus influenzae serotype replacement in Europe after introduction of the Hib conjugate vaccine
Lancet Infect Dis
NTHi-Watch
Variation and type specificity in the bacterial species Hemophilus influenzae
J Exp Med
Complete sequence of the cap locus of Haemophilus influenzae serotype b and nonencapsulated b capsule-negative variants
Infect Immun
Use of bexB to detect the capsule locus in Haemophilus influenzae
J Clin Microbiol
Capsule gene analysis of invasive Haemophilus influenzae: accuracy of serotyping and prevalence of IS1016 among nontypeable isolates
J Clin Microbiol
A taxonomic study of the genus Haemophilus, with the proposal of a new species
J Gen Microbiol
Molecular epidemiology of Haemophilus influenzae type b strains
Characterization of encapsulated and noncapsulated Haemophilus influenzae and determination of phylogenetic relationships by multilocus sequence typing
J Clin Microbiol
Nontypeable Haemophilus influenzae in carriage and disease: a difference in IgA1 protease activity levels
JAMA
Thätigkeit der deutschen Cholerakommission in Aegypten und Ostindien
Wien Med Wochenschr
The bacillus of acute conjunctival catarrh
Arch Ophthalmol
Brazilian purpuric fever: Haemophilus aegyptius bacteraemia complicating purulent conjunctivitis
MMWR Morb Mortal Wkly Rep
Relationships of nontypeable Haemophilus influenzae strains to hemolytic and nonhemolytic Haemophilus haemolyticus strains
J Clin Microbiol
Evaluation of new biomarker genes for differentiating Haemophilus influenzae from Haemophilus haemolyticus
J Clin Microbiol
MALDI-TOF MS distinctly differentiates nontypable Haemophilus influenzae from Haemophilus haemolyticus
PLoS One
Rapid discrimination of Haemophilus influenzae, H. parainfluenzae, and H. haemolyticus by fluorescence in situ hybridization (FISH) and two matrix-assisted laser-desorption-ionization time-of-flight mass spectrometry (MALDI-TOF-MS) platforms
PLoS One
Molecular surveillance of true nontypeable Haemophilus influenzae: an evaluation of PCR screening assays
PLoS One
Active Bacterial Core surveillance
Community-wide vaccination with the heptavalent pneumococcal conjugate significantly alters the microbiology of acute otitis media
Pediatr Infect Dis J
Efficacy of a pneumococcal conjugate vaccine against acute otitis media
N Engl J Med
Identification and characterization of the bacterial etiology of clinically problematic acute otitis media after tympanocentesis or spontaneous otorrhea in German children
BMC Infect Dis
Seasonal distribution of otitis media pathogens among Costa Rican children
Pediatr Infect Dis J
The challenge of recalcitrant acute otitis media: pathogens, resistance, and treatment strategy
Pediatr Infect Dis J
Non-capsulated and capsulated Haemophilus influenzae in children with acute otitis media in Venezuela: a prospective epidemiological study
BMC Infect Dis
Non-typeable Haemophilus influenzae and Streptococcus pneumoniae as primary causes of acute otitis media in Colombian children: a prospective study
BMC Infect Dis
Detection of human metapneumovirus from children with acute otitis media
Pediatr Infect Dis J
Increasing bacterial resistance in pediatric acute conjunctivitis (1997–1998)
Antimicrob Agents Chemother
Clinical and bacterial characteristics of acute bacterial conjunctivitis in children in the antibiotic resistance era
Pediatr Infect Dis J
Acute conjunctivitis
Pediatrics Rev
Cited by (246)
Bacitracin agar vs. oleandomycin disk supplemented chocolate agar for the recovery of Haemophilus influenzae in diagnostic samples: A prospective comparison
2024, Diagnostic Microbiology and Infectious DiseaseHaemophilus influenzae
2023, Molecular Medical Microbiology, Third Edition