- Email: [email protected]
Nontypeable Haemophilus influenzae (NTHi)
Trends in Microbiology | Microbe of the Month
Nontypeable [2_TD$IF]Haemophilus influenzae[3_TD$IF] (NTHi) Lauren O. Bakaletz1,2,* and Laura A. Novotny1,2 1
Center for Microbial Pathogenesis, The Research Institute at Nationwide Children’s Hospital, Columbus, Ohio, USA The Ohio State University College of Medicine, Department of Pediatrics, Columbus, Ohio, USA
2
KEY FACTS:
Haemophilus means ‘blood-lover’. Humans are the only natural hosts. Eye (conjuncvis)
Meninges (meningis)
Aerobe or facultative anaerobe.
Sinuses (sinusis)
Mastoid (mastoidis)
Requires protoporphyrin IX and nicotinamide adenine dinucleotide.
Nasopharynx: site of colonizaon, no signs of disease unll viral dysregulaon of host physical and innate immune defeneses
Middle ear (os media)
[17_TD$IF]Nonencapsulated, considered ‘[9_TD$IF]nontypeable’. Exhibits twitching motility (Bakaletz [18_TD$IF]et al., 2005). Expresses lipooligosaccharide (LOS).
Bronchus (bronchis)
Lungs (exacerbaons in CF, chronic cough, pneumonia)
Lungs (exacerbaons of COPD)
Commensal
Predominant diseases by NTHi
Less prevalent disease by NTHi
Infecons in developing world
In this infographic the diseases caused by nontypeable [2_TD$IF]Haemophilus influenzae[4_TD$IF] (NTHi), including otitis media[5_TD$IF], are discussed. Encapsulated type b [6_TD$IF]Haemophilus influenzae (Hib) was responsible for [7_TD$IF]most of the invasive disease (meningitis) prior to the use of Hib vaccines. As Hib vaccines have no effect on infections due to [8_TD$IF]nontypeable H. influenzae (NTHi), in areas where Hib vaccines are used, [9_TD$IF]nontypeable strains are now the most common cause of invasive disease. Moreover, NTHi contributes to the 21 [10_TD$IF]000 otitis media (OM)-associated deaths per year. Due to this collective global morbidity and mortality, concerted vaccine development is underway. In addition to preventing disease, an effective vaccine will likely help [1_TD$IF]to mitigate the global crisis of antibiotic resistance. Since 1973, ampicillin resistance due to [12_TD$IF]NTHi’s production of b-lactamase has been recognized[13_TD$IF]; however, a significant concern is the more recent emergence and spread of b-lactamase-negative-ampicillin-resistant (BLNAR) strains in many regions of the world. As such, H. influenzae is one of 12 bacterial pathogens that are considered priority pathogens by the [14_TD$IF]World Health Organization. TAXONOMY AND CLASSIFICATION: [15_TD$IF]SUPERKINGDOM: Bacteria PHYLUM: Proteobacteria CLASS: Gammaproteobacteria [16_TD$IF]ORDER: Pasteurellales FAMILY: Pasteurellaceae GENUS: Haemophilus SPECIES: influenzae Gram-negative coccobacillus or rod, pleomorphic
Naturally competent. Demonstrates classic phase variation as well as via the ‘phasevarion’. Highly diverse genotypically and phenotypically. Genome is 1.8 [19_TD$IF]Mb; the first free-living organism whose genome was fully sequenced. DISEASE FACTS:
Original isolation from sputum during the influenza virus pandemic of [20_TD$IF]1889–1892 led to the mistaken conclusion that H. influenzae was responsible. NTHi is a common commensal of the human nasopharynx. NTHi induces a polymicrobial disease typically due to concurrent or predisposing upper respiratory tract viral infection. Major causative agent of OM in children[21_TD$IF], and exacerbations of chronic obstructive pulmonary disease (COPD) in adults[2_TD$IF], resulting in significant global morbidity. Also causes exacerbations of cystic fibrosis (CF), bronchitis, chronic cough[23_TD$IF], and conjunctivitis. In the very young and the elderly, bacteremia and pneumonia also occur. Wide use of pneumococcal polysaccharide conjugate vaccines (PCVs) has shifted the microbiology of OM, resulting in a higher proportion of cases due to NTHi. Antibiotic use for both COPD and OM is a predominant driving force for the emergence of antibiotic[24_TD$IF]-resistant bacteria. *Correspondence: [email protected] (L.O. Bakaletz).
Trends in Microbiology, Month Year, Vol. xx, No. yy
© 2018 Elsevier Ltd. All rights reserved.
https://doi.org/10.1016/j.tim.2018.05.001
1
Trends in Microbiology | Microbe of the Month Acknowledgments Scanning electron micrograph of a bacterial biofilm formed by NTHi on the surface of polarized human airway epithelial cells from Kenneth L. Brockman, PhD. Resources http://www.who.int/medicines/publications/global-priority-list-antibiotic-resistant-bacteria/en/ Literature 1. Bakaletz, L.O. et al. (2005) Demonstration of Type IV pilus expression and a twitching phenotype by Haemophilus influenzae. Infect. Immun. 73, 1635–1643 2. Srikhanta, Y.N. et al. (2005) The phasevarion: a genetic system controlling coordinated, random switching of expression of multiple genes. Proc. Natl. Acad. Sci. U. S. A. 102, 5547–5551 3. Fleischmann, R.D. et al. (1995) Whole-genome random sequencing and assembly of Haemophilus influenzae Rd. Science 269, 496–512 4. Murphy, T.F. (2015) Vaccines for nontypeable Haemophilus influenzae: the future is now. Clin. Vaccine Immunol. 22, 459–466 5. Van Eldere, J. et al. (2014) Non-typeable Haemophilus influenzae, an under-recognised pathogen. Lancet Infect. Dis. 14, 1281–1292 6. Dagan, R. and Klugman, K.P. (2008) Impact of conjugate pneumococcal vaccines on antibiotic resistance. Lancet Infect. Dis. 8, 785–795 7. Wilby, K.J. and Werry, D. (2012) A review of the effect of immunization programs on antimicrobial utilization. Vaccine 30, 6509–6514 8. World Health Organization (2004) Chronic Suppurative Otitis Media: Burden of Illness and Management Options. Chronicsuppurativeotitis_media.pdf
http://www.who.int/pbd/publications/
9. Clarke, C. et al. (2017) Impact of protein D-containing pneumococcal conjugate vaccines on non-typeable Haemophilus influenzae acute otitis media and carriage. Expert Rev. Vaccines 16, 1–14
2
Trends in Microbiology, Month Year, Vol. xx, No. yy
© 2018 Elsevier Ltd. All rights reserved.
https://doi.org/10.1016/j.tim.2018.05.001
Nontypeable [2_TD$IF]Haemophilus influenzae[3_TD$IF] (NTHi) Lauren O. Bakaletz1,2,* and Laura A. Novotny1,2 1
Center for Microbial Pathogenesis, The Research Institute at Nationwide Children’s Hospital, Columbus, Ohio, USA The Ohio State University College of Medicine, Department of Pediatrics, Columbus, Ohio, USA
2
KEY FACTS:
Haemophilus means ‘blood-lover’. Humans are the only natural hosts. Eye (conjuncvis)
Meninges (meningis)
Aerobe or facultative anaerobe.
Sinuses (sinusis)
Mastoid (mastoidis)
Requires protoporphyrin IX and nicotinamide adenine dinucleotide.
Nasopharynx: site of colonizaon, no signs of disease unll viral dysregulaon of host physical and innate immune defeneses
Middle ear (os media)
[17_TD$IF]Nonencapsulated, considered ‘[9_TD$IF]nontypeable’. Exhibits twitching motility (Bakaletz [18_TD$IF]et al., 2005). Expresses lipooligosaccharide (LOS).
Bronchus (bronchis)
Lungs (exacerbaons in CF, chronic cough, pneumonia)
Lungs (exacerbaons of COPD)
Commensal
Predominant diseases by NTHi
Less prevalent disease by NTHi
Infecons in developing world
In this infographic the diseases caused by nontypeable [2_TD$IF]Haemophilus influenzae[4_TD$IF] (NTHi), including otitis media[5_TD$IF], are discussed. Encapsulated type b [6_TD$IF]Haemophilus influenzae (Hib) was responsible for [7_TD$IF]most of the invasive disease (meningitis) prior to the use of Hib vaccines. As Hib vaccines have no effect on infections due to [8_TD$IF]nontypeable H. influenzae (NTHi), in areas where Hib vaccines are used, [9_TD$IF]nontypeable strains are now the most common cause of invasive disease. Moreover, NTHi contributes to the 21 [10_TD$IF]000 otitis media (OM)-associated deaths per year. Due to this collective global morbidity and mortality, concerted vaccine development is underway. In addition to preventing disease, an effective vaccine will likely help [1_TD$IF]to mitigate the global crisis of antibiotic resistance. Since 1973, ampicillin resistance due to [12_TD$IF]NTHi’s production of b-lactamase has been recognized[13_TD$IF]; however, a significant concern is the more recent emergence and spread of b-lactamase-negative-ampicillin-resistant (BLNAR) strains in many regions of the world. As such, H. influenzae is one of 12 bacterial pathogens that are considered priority pathogens by the [14_TD$IF]World Health Organization. TAXONOMY AND CLASSIFICATION: [15_TD$IF]SUPERKINGDOM: Bacteria PHYLUM: Proteobacteria CLASS: Gammaproteobacteria [16_TD$IF]ORDER: Pasteurellales FAMILY: Pasteurellaceae GENUS: Haemophilus SPECIES: influenzae Gram-negative coccobacillus or rod, pleomorphic
Naturally competent. Demonstrates classic phase variation as well as via the ‘phasevarion’. Highly diverse genotypically and phenotypically. Genome is 1.8 [19_TD$IF]Mb; the first free-living organism whose genome was fully sequenced. DISEASE FACTS:
Original isolation from sputum during the influenza virus pandemic of [20_TD$IF]1889–1892 led to the mistaken conclusion that H. influenzae was responsible. NTHi is a common commensal of the human nasopharynx. NTHi induces a polymicrobial disease typically due to concurrent or predisposing upper respiratory tract viral infection. Major causative agent of OM in children[21_TD$IF], and exacerbations of chronic obstructive pulmonary disease (COPD) in adults[2_TD$IF], resulting in significant global morbidity. Also causes exacerbations of cystic fibrosis (CF), bronchitis, chronic cough[23_TD$IF], and conjunctivitis. In the very young and the elderly, bacteremia and pneumonia also occur. Wide use of pneumococcal polysaccharide conjugate vaccines (PCVs) has shifted the microbiology of OM, resulting in a higher proportion of cases due to NTHi. Antibiotic use for both COPD and OM is a predominant driving force for the emergence of antibiotic[24_TD$IF]-resistant bacteria. *Correspondence: [email protected] (L.O. Bakaletz).
Trends in Microbiology, Month Year, Vol. xx, No. yy
© 2018 Elsevier Ltd. All rights reserved.
https://doi.org/10.1016/j.tim.2018.05.001
1
Trends in Microbiology | Microbe of the Month Acknowledgments Scanning electron micrograph of a bacterial biofilm formed by NTHi on the surface of polarized human airway epithelial cells from Kenneth L. Brockman, PhD. Resources http://www.who.int/medicines/publications/global-priority-list-antibiotic-resistant-bacteria/en/ Literature 1. Bakaletz, L.O. et al. (2005) Demonstration of Type IV pilus expression and a twitching phenotype by Haemophilus influenzae. Infect. Immun. 73, 1635–1643 2. Srikhanta, Y.N. et al. (2005) The phasevarion: a genetic system controlling coordinated, random switching of expression of multiple genes. Proc. Natl. Acad. Sci. U. S. A. 102, 5547–5551 3. Fleischmann, R.D. et al. (1995) Whole-genome random sequencing and assembly of Haemophilus influenzae Rd. Science 269, 496–512 4. Murphy, T.F. (2015) Vaccines for nontypeable Haemophilus influenzae: the future is now. Clin. Vaccine Immunol. 22, 459–466 5. Van Eldere, J. et al. (2014) Non-typeable Haemophilus influenzae, an under-recognised pathogen. Lancet Infect. Dis. 14, 1281–1292 6. Dagan, R. and Klugman, K.P. (2008) Impact of conjugate pneumococcal vaccines on antibiotic resistance. Lancet Infect. Dis. 8, 785–795 7. Wilby, K.J. and Werry, D. (2012) A review of the effect of immunization programs on antimicrobial utilization. Vaccine 30, 6509–6514 8. World Health Organization (2004) Chronic Suppurative Otitis Media: Burden of Illness and Management Options. Chronicsuppurativeotitis_media.pdf
http://www.who.int/pbd/publications/
9. Clarke, C. et al. (2017) Impact of protein D-containing pneumococcal conjugate vaccines on non-typeable Haemophilus influenzae acute otitis media and carriage. Expert Rev. Vaccines 16, 1–14
2
Trends in Microbiology, Month Year, Vol. xx, No. yy
© 2018 Elsevier Ltd. All rights reserved.
https://doi.org/10.1016/j.tim.2018.05.001