Review
Non-typeable Haemophilus influenzae, an under-recognised pathogen

https://doi.org/10.1016/S1473-3099(14)70734-0Get rights and content

Summary

Non-typeable Haemophilus influenzae (NTHi) is a major cause of mucosal infections such as otitis media, sinusitis, conjunctivitis, and exacerbations of chronic obstructive pulmonary disease. In some regions, a strong causal relation links this pathogen with infections of the lower respiratory tract. In the past 20 years, a steady but constant increase has occurred in invasive NTHi worldwide, with perinatal infants, young children, and elderly people most at risk. Individuals with underlying comorbidities are most susceptible and infection is associated with high mortality. β-lactamase production is the predominant mechanism of resistance. However, the emergence and spread of β-lactamase-negative ampicillin-resistant strains in many regions of the world is of substantial concern, potentially necessitating changes to antibiotic treatment guidelines for community-acquired infections of the upper and lower respiratory tract and potentially increasing morbidity associated with invasive NTHi infections. Standardised surveillance protocols and typing methodologies to monitor this emerging pathogen should be implemented. International scientific organisations need to raise the profile of NTHi and to document the pathobiology of this microbe.

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

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

References (153)

  • SP Wiertsema et al.

    Predominance of nontypeable Haemophilus influenzae in children with otitis media following introduction of a 3+0 pneumococcal conjugate vaccine schedule

    Vaccine

    (2011)
  • R Prymula et al.

    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

    (2009)
  • FW Otten et al.

    Treatment of chronic maxillary sinusitis in children

    Int J Pediatr Otorhinolaryngol

    (1988)
  • JB Soriano et al.

    Chronic obstructive pulmonary disease: a worldwide problem

    Med Clin North Am

    (2012)
  • MK Tandon et al.

    Oral immunotherapy with inactivated nontypeable Haemophilus influenzae reduces severity of acute exacerbations in severe COPD

    Chest

    (2010)
  • JM Marchant et al.

    Evaluation and outcome of young children with chronic cough

    Chest

    (2006)
  • KN Priftis et al.

    Bacterial bronchitis caused by Streptococcus pneumoniae and nontypable Haemophilus influenzae in children: the impact of vaccination

    Chest

    (2013)
  • SH Abman et al.

    Early bacteriologic, immunologic, and clinical courses of young infants with cystic fibrosis identified by neonatal screening

    J Pediatr

    (1991)
  • R Cardines et al.

    Haemophilus influenzae in children with cystic fibrosis: antimicrobial susceptibility, molecular epidemiology, distribution of adhesins and biofilm formation

    Int J Med Microbiol

    (2012)
  • F Resman et al.

    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

    (2011)
  • S Ladhani et al.

    No evidence for Haemophilus influenzae serotype replacement in Europe after introduction of the Hib conjugate vaccine

    Lancet Infect Dis

    (2008)
  • NTHi-Watch

  • M Pittman

    Variation and type specificity in the bacterial species Hemophilus influenzae

    J Exp Med

    (1931)
  • SW Satola et al.

    Complete sequence of the cap locus of Haemophilus influenzae serotype b and nonencapsulated b capsule-negative variants

    Infect Immun

    (2003)
  • GS Davis et al.

    Use of bexB to detect the capsule locus in Haemophilus influenzae

    J Clin Microbiol

    (2011)
  • SW Satola et al.

    Capsule gene analysis of invasive Haemophilus influenzae: accuracy of serotyping and prevalence of IS1016 among nontypeable isolates

    J Clin Microbiol

    (2007)
  • M Kilian

    A taxonomic study of the genus Haemophilus, with the proposal of a new species

    J Gen Microbiol

    (1976)
  • L van Alphen

    Molecular epidemiology of Haemophilus influenzae type b strains

  • E Meats et al.

    Characterization of encapsulated and noncapsulated Haemophilus influenzae and determination of phylogenetic relationships by multilocus sequence typing

    J Clin Microbiol

    (2003)
  • S Vitovski et al.

    Nontypeable Haemophilus influenzae in carriage and disease: a difference in IgA1 protease activity levels

    JAMA

    (2002)
  • R Koch

    Thätigkeit der deutschen Cholerakommission in Aegypten und Ostindien

    Wien Med Wochenschr

    (1883)
  • JN Weeks

    The bacillus of acute conjunctival catarrh

    Arch Ophthalmol

    (1886)
  • Brazilian purpuric fever: Haemophilus aegyptius bacteraemia complicating purulent conjunctivitis

    MMWR Morb Mortal Wkly Rep

    (1986)
  • KW McCrea et al.

    Relationships of nontypeable Haemophilus influenzae strains to hemolytic and nonhemolytic Haemophilus haemolyticus strains

    J Clin Microbiol

    (2008)
  • MJ Theodore et al.

    Evaluation of new biomarker genes for differentiating Haemophilus influenzae from Haemophilus haemolyticus

    J Clin Microbiol

    (2012)
  • B Zhu et al.

    MALDI-TOF MS distinctly differentiates nontypable Haemophilus influenzae from Haemophilus haemolyticus

    PLoS One

    (2013)
  • H Frickmann et al.

    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

    (2013)
  • MJ Binks et al.

    Molecular surveillance of true nontypeable Haemophilus influenzae: an evaluation of PCR screening assays

    PLoS One

    (2012)
  • Active Bacterial Core surveillance

  • SL Block et al.

    Community-wide vaccination with the heptavalent pneumococcal conjugate significantly alters the microbiology of acute otitis media

    Pediatr Infect Dis J

    (2004)
  • J Eskola et al.

    Efficacy of a pneumococcal conjugate vaccine against acute otitis media

    N Engl J Med

    (2001)
  • G Grevers et al.

    Identification and characterization of the bacterial etiology of clinically problematic acute otitis media after tympanocentesis or spontaneous otorrhea in German children

    BMC Infect Dis

    (2012)
  • S Guevara et al.

    Seasonal distribution of otitis media pathogens among Costa Rican children

    Pediatr Infect Dis J

    (2008)
  • E Leibovitz

    The challenge of recalcitrant acute otitis media: pathogens, resistance, and treatment strategy

    Pediatr Infect Dis J

    (2007)
  • L Naranjo et al.

    Non-capsulated and capsulated Haemophilus influenzae in children with acute otitis media in Venezuela: a prospective epidemiological study

    BMC Infect Dis

    (2012)
  • A Sierra et al.

    Non-typeable Haemophilus influenzae and Streptococcus pneumoniae as primary causes of acute otitis media in Colombian children: a prospective study

    BMC Infect Dis

    (2011)
  • A Suzuki et al.

    Detection of human metapneumovirus from children with acute otitis media

    Pediatr Infect Dis J

    (2005)
  • SL Block et al.

    Increasing bacterial resistance in pediatric acute conjunctivitis (1997–1998)

    Antimicrob Agents Chemother

    (2000)
  • N Buznach et al.

    Clinical and bacterial characteristics of acute bacterial conjunctivitis in children in the antibiotic resistance era

    Pediatr Infect Dis J

    (2005)
  • F Gigliotti

    Acute conjunctivitis

    Pediatrics Rev

    (1995)
  • Cited by (246)

    • Haemophilus influenzae

      2023, Molecular Medical Microbiology, Third Edition
    View all citing articles on Scopus
    View full text