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Haemophilus influenzae was proposed by Pfeiffer in 1892 as the etiologic agent of influenza because of its recovery from the respiratory tracts of persons with that disease. It was later identified as a major bacterial cause of pneumonia and meningitis in children and immunocompromised or chronically ill adults. H. influenzae type b (Hib) was the most common cause of bacterial meningitis and invasive bacterial disease in children in the United States before the introduction of Hib polysaccharide-protein conjugate vaccines in the late 1980s. Routine infant immunization against Hib has led to the near elimination of Hib disease in the United States.1,2 Of the 194 WHO member countries, 192 (99%) have introduced conjugate Hib vaccine, which contributed to substantial declines in Hib deaths globally.3–5 The success of the Hib conjugate vaccines has paved the way for a new generation of vaccines against the other major bacterial diseases of children, Streptococcus pneumoniae and Neisseria meningitidis. However, in the post-Hib vaccine era, increases in nonserotype b H. influenzae infections, particularly H. influenzae serotype a (Hia) and nontypeable H. influenzae, have occurred in some countries, including Canada and the United States.2,6
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H. influenzae is a nonmotile, gram-negative bacterium with varied form, appearing as cocci to small rods in clinical specimens. It can be difficult to stain and may be confused with gram-positive diplococci in spinal fluid. In vitro culture requires the use of specialized media supplemented with essential growth factors (hemin or “factor X” and nicotinamide adenine dinucleotide or “factor V”) and a carbon dioxide rich atmosphere.
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H. influenzae are classified into six capsular serotypes (designated a, b, c, d, e, and f) that were first identified by Pittman in 1931. There are also unencapsulated strains that are referred to as “nontypeable.” In clinical or reference laboratories, serotyping can be performed using slide agglutination serotyping (SAST), which takes advantage of type-specific agglutination of organisms by antisera. Although used since the 1930s, this technique requires subjective interpretation, and cross-reactivity can result in misclassification.7 DNA-based methods, such as the polymerase chain reaction (PCR) and whole genome sequencing (WGS), can also be used to determine capsular genotypes. Real-time PCR is highly sensitive and specific for distinguishing H. influenzae capsular genotypes. Both real-time PCR and WGS have shown good agreement with SAST in determining H. influenzae capsule types.8
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Antibiotic resistance among isolates is widespread, but prevalence varies geographically. H. influenzae strains may acquire resistance to common beta-lactam antibiotics, such as penicillin and ampicillin, via plasmids containing genes for beta lactamase. Approximately one-third of U.S. invasive isolates are β-lactamase positive.9,10 In two global assessments, 16–17% of isolates from the respiratory tract were β-lactamase positive, ranging from 2% in Italy to 65% in South Korea.11,12 In addition, β-lactamase-negative ampicillin-resistant (BLNAR) strains have been detected. While BLNAR strains are rare overall,12,13 nearly 40% of H. influenzae...