Invasive Haemophilus influenzae Infections after 3 Decades of Hib Protein Conjugate Vaccine Use

Slack, Mary P. E.; Cripps, Allan W.; Grimwood, Keith; Mackenzie, Grant; Ulanova, Marina

doi:10.1128/cmr.00028-21

Cited by 33 publications

(96 citation statements)

References 194 publications

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“…Untreated septic arthritis often results in reduced and potentially impaired mobility [ 39 , 41 , 43 ], and if the child did in fact also suffer from untreated meningitis, neurological damage and hearing loss cannot be excluded [ 45 , 46 ]. In children, untreated bacterial meningitis can lead to death in up to 5% of cases and to permanent disabilities in up to 40% of cases [ 5 , 47 ].…”

Section: Discussionmentioning

confidence: 99%

“…Further sampling will also be needed to explore the overall genetic diversity and prevalence of the species and the Hib-II clade in ancient populations. Genomes from different periods of human history could offer us a unique opportunity to study the evolution of the pathogen’s virulence and give us further insights into the expansion and rise of non-typeable strains, which have recently been emerging as the main cause of invasive H. influenzae infections [ 1 , 6 , 47 ].…”

Section: Discussionmentioning

confidence: 99%

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An invasive Haemophilus influenzae serotype b infection in an Anglo-Saxon plague victim

et al. 2022

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Background The human pathogen Haemophilus influenzae was the main cause of bacterial meningitis in children and a major cause of worldwide infant mortality before the introduction of a vaccine in the 1980s. Although the occurrence of serotype b (Hib), the most virulent type of H. influenzae, has since decreased, reports of infections with other serotypes and non-typeable strains are on the rise. While non-typeable strains have been studied in-depth, very little is known of the pathogen’s evolutionary history, and no genomes dating prior to 1940 were available. Results We describe a Hib genome isolated from a 6-year-old Anglo-Saxon plague victim, from approximately 540 to 550 CE, Edix Hill, England, showing signs of invasive infection on its skeleton. We find that the genome clusters in phylogenetic division II with Hib strain NCTC8468, which also caused invasive disease. While the virulence profile of our genome was distinct, its genomic similarity to NCTC8468 points to mostly clonal evolution of the clade since the 6th century. We also reconstruct a partial Yersinia pestis genome, which is likely identical to a published first plague pandemic genome of Edix Hill. Conclusions Our study presents the earliest genomic evidence for H. influenzae, points to the potential presence of larger genomic diversity in the phylogenetic division II serotype b clade in the past, and allows the first insights into the evolutionary history of this major human pathogen. The identification of both plague and Hib opens questions on the effect of plague in immunocompromised individuals already affected by infectious diseases.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

An invasive Haemophilus influenzae serotype b infection in an Anglo-Saxon plague victim

et al. 2022

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“…Reduced vaccine response is one of the diagnostic criteria for CVID and the therapeutic potential of active immunization in this patient group remains questionable. Moreover, no vaccine is available for NTHi, which currently constitute the major concern in CVID patients ( Slack et al., 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Case Report: Whole-Genome Sequencing of Serially Collected Haemophilus influenzae From a Patient With Common Variable Immunodeficiency Reveals Within-Host Evolution of Resistance to Trimethoprim-Sulfamethoxazole and Azithromycin After Prolonged Treatment With These Antibiotics

Lindemann

Mylvaganam

Oppegaard

et al. 2022

Front. Cell. Infect. Microbiol.

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We report within-host evolution of antibiotic resistance to trimethoprim-sulfamethoxazole and azithromycin in a nontypeable Haemophilus influenzae strain from a patient with common variable immunodeficiency (CVID), who received repeated or prolonged treatment with these antibiotics for recurrent respiratory tract infections. Whole-genome sequencing of three longitudinally collected sputum isolates during the period April 2016 to January 2018 revealed persistence of a strain of sequence type 2386. Reduced susceptibility to trimethoprim-sulfamethoxazole in the first two isolates was associated with mutations in genes encoding dihydrofolate reductase (folA) and its promotor region, dihydropteroate synthase (folP), and thymidylate synthase (thyA), while subsequent substitution of a single amino acid in dihydropteroate synthase (G225A) rendered high-level resistance in the third isolate from 2018. Azithromycin co-resistance in this isolate was associated with amino acid substitutions in 50S ribosomal proteins L4 (W59R) and L22 (G91D), possibly aided by a substitution in AcrB (A604E) of the AcrAB efflux pump. All three isolates were resistant to aminopenicillins and cefotaxime due to TEM-1B beta-lactamase and identical alterations in penicillin-binding protein 3. Further resistance development to trimethoprim-sulfamethoxazole and azithromycin resulted in a multidrug-resistant phenotype. Evolution of multidrug resistance due to horizontal gene transfer and/or spontaneous mutations, along with selection of resistant subpopulations is a particular risk in CVID and other patients requiring repeated and prolonged antibiotic treatment or prophylaxis. Such challenging situations call for careful antibiotic stewardship together with supportive and supplementary treatment. We describe the clinical and microbiological course of events in this case report and address the challenges encountered.

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“…Asymptomatic colonization begins in the upper airways, but it can spread through the respiratory tract and lead to invasive infections. The polysaccharide capsule vaccine has driven the almost complete disappearance of capsulated H. influenzae type b (Hib) in countries with established child immunization programs ( 1 , 2 ). Instead, other H. influenzae serotypes and nontypeable strains (NTHi), untargeted by the Hib vaccine, emerge as important causes of infections.…”

Section: Introductionmentioning

confidence: 99%

Interrogation of Essentiality in the Reconstructed Haemophilus influenzae Metabolic Network Identifies Lipid Metabolism Antimicrobial Targets: Preclinical Evaluation of a FabH β-Ketoacyl-ACP Synthase Inhibitor

et al. 2022

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Antimicrobial resistance drives the need of synergistically combined powerful computational tools and experimental work to accelerate target identification and drug development. Here, we present a high-quality metabolic model of H. influenzae and show its usefulness both as a computational framework for large experimental data set contextualization and as a tool to discover condition-independent drug targets.

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Invasive Haemophilus influenzae Infections after 3 Decades of Hib Protein Conjugate Vaccine Use

Abstract: Haemophilus influenzae serotype b (Hib) was previously the most common cause of bacterial meningitis and an important etiologic agent of pneumonia in children aged <5 years. Its major virulence factor is the polyribosyl ribitol phosphate (PRP) polysaccharide capsule.

Cited by 33 publications

References 194 publications

An invasive Haemophilus influenzae serotype b infection in an Anglo-Saxon plague victim

An invasive Haemophilus influenzae serotype b infection in an Anglo-Saxon plague victim

Case Report: Whole-Genome Sequencing of Serially Collected Haemophilus influenzae From a Patient With Common Variable Immunodeficiency Reveals Within-Host Evolution of Resistance to Trimethoprim-Sulfamethoxazole and Azithromycin After Prolonged Treatment With These Antibiotics

Interrogation of Essentiality in the Reconstructed Haemophilus influenzae Metabolic Network Identifies Lipid Metabolism Antimicrobial Targets: Preclinical Evaluation of a FabH β-Ketoacyl-ACP Synthase Inhibitor

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