Haemophilus influenzae

OVERVIEW: What every clinician needs to know

Pathogen name and classification

Haemophilus influenzae – a small Gram negative coccobacillus isolated primarily from the human respiratory tract

Six serotypes, based on capsular polysaccharide, have been identified (serotypes a through f). Type b strains cause invasive disease, most commonly meningitis, predominantly in infants.
Non-encapsulated or so called nontypeable strains frequently colonize the upper respiratory tract of children and adults and cause disease by contiguous spread in the respiratory tract; manifestations include otitis media in children, sinusitis in children and adults, and exacerbations in adults with chronic obstructive pulmonary disease (COPD).
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What is the best treatment?

Approximately 30% of nontypeable strains produce ß-lactamase, but substantial geographic variation is observed. As a result, ampicillin and amoxicillin should be used only when the susceptibility of the infecting isolate is known. Otitis media and exacerbations of COPD are usually treated empirically.
Many infections caused by nontypeable H. influenzae, including otitis media in children and exacerbations in adults with COPD, can be treated with oral antimicrobial agents. Oral agents active against nontypeable strains include amoxicillin-clavulanate, fluoroquinolones, macrolides (e.g., azithromycin, clarithromycin), and various extended spectrum cephalosporins (e.g., cefixime, cefpodoxime, loracarbef, cefuroxime).
Parenteral antibiotic therapy should be used for invasive infections caused by nontypeable strains. Agents with activity include cephalosporins (e.g., ceftriaxone, cefuroxime, ceftazidime, cefotaxime), ampicillin-sulbactam, fluoroquinolones and azithromycin.
The favored regimens for treatment of invasive infections caused by type b strains, including meningitis and epiglottitis, are intravenous cefotaxime or ceftriaxone.
Mechanisms of antimicrobial resistance:

The most common mechanism of resistance to penicillins in isolates from the United States is production of ß-lactamase.

A second mechanism of penicillin resistance is alteration in penicillin binding proteins. This mechanism of resistance is being observed with increasing frequency, especially in Japan and Europe.

How do patients contract this infection, and how do I prevent spread to other patients?

Epidemiology

H. influenzae is isolated exclusively from humans. No animal or environmental sources have been identified.
Nontypeable strains are common colonizers of the nasopharynx of children. Colonization is a dynamic process with continuous acquisition and clearance of strains. Essentially all humans are colonized at some time.
H. infuenzae is transmitted person-to-person within families and among children. Children who attend daycare centers are colonized at a higher rate compared to control children.
Nontypeable H. influenzae is the first or second most common cause of otitis media in children. Otitis media is the most common bacterial infection in children and is the most common reason for children to receive antibiotic therapy in the United States.
The widespread administration of pneumococcal polysaccharide vaccines in developed countries is causing changes in patterns of nasopharyngeal colonization and the distribution of bacterial pathogens that cause otitis media. An increase in the proportion of otitis media caused by H. influenzae has occurred as a result of a reduction of colonization by vaccine serotypes of Streptococcus pneumoniae with “replacement” by nonvaccine serotypes of S. pneumoniae, nontypeable H. infuenzae, and Moraxella catarrhalis.
Nontypeable H. influenzae is the most common cause of exacerbations of COPD in adults. Approximately 24 million Americans have COPD and experience intermittent exacerbations, many caused by bacterial infection. Thus, H. influenzae infections are highly prevalent among adults with COPD.
The epidemiology of encapsulated serotype type b strains of H. influenzae differs markedly from that of nontypeable strains. The development of highly effective H. influenzae type b (Hib) conjugate vaccines and their widespread use since the 1990s has dramatically reduced the prevalence of meningitis and invasive infections in countries in which the vaccine is used.
The Hib conjugate vaccines also reduce or eliminate nasopharyngeal colonization by Hib strains, and this reduction contributes to the “herd effect” observed with these vaccines. The vaccines have almost eradicated invasive Hib infections in children younger than 5 years of age in the United States.
H. influenzae serotype b strains remain a common cause of meningitis and other invasive infections, such as epiglotitis and bacteremia in countries that do not have Hib conjugate vaccine programs.

Infection control issues

H. influenzae is transmitted person-to-person. Careful hand washing and respiratory hygiene measures are appropriate in an effort to reduce the likelihood of transmission.
Conjugate vaccines for invasive Hib infections in infants and children are highly effective. All children should be immunized with a conjugate vaccine beginning at 2 months of age. Two conjugate vaccines are currently licensed and available in the United States. Clinicians should consult the single set of guidelines approved by Advisory Committee on Immunization Practices, the American Academy of Pediatrics, and the American Academy of Family Physicians.
There are no vaccines currently licensed for nontypeable H. influenzae in the United States. Clinical trials with a vaccine that contains protein D, a conserved surface protein have shown partial efficacy. A vaccine that includes this protein has recently been licensed in Europe. Additional progress in vaccine development for nontypeable H. influenzae is anticipated.
In the absence of prior immunization, household contacts at younger than 4 years of age of those with invasive Hib infection have a substantial increased incidence of disease. Prophylaxis with rifampin at 20 mg/kg once daily for 4 days eradicates the carrier state in 95% of carriers and reduces the rate of secondary infections in households. Prophylaxis is recommended for all household members, including adults (except pregnant women), when there has been contact with an index case of Hib disease by a household member who is younger than 4 years of age and whose immunization status for Hib is incomplete. Clinicians should consult guidelines of the Centers for Disease Control and American Academy of Pediatrics.

What host factors protect against this infection?

Recurrence is a characteristic feature of infection with nontypeable H. influenzae. Children and adults develop strain-specific protection following infection, accounting for susceptibility to recurrent infection by different strains. The mechanisms of protective immunity to nontypeable strains are complex and incompletely understood.
Nontypeable H. infuenzae infections occur in specific host settings. In children, bacterial otitis media is frequently preceded by viral upper respiratory infection, which creates conditions in the upper airway for colonizing nontypeable H. influenzae to migrate from the nasopharynx to the middle ear via the Eustachian tube.
Nontypeable H. influenzae is the predominant bacterial pathogen in adults with COPD. The healthy human respiratory tract is sterile below the vocal cords. Impaired mucociliary clearance in COPD results in colonization of the lower airways with H. influenzae as the most common pathogen. Chronic colonization of the airways contributes to the airway inflammation that is a hallmark of COPD.
Intermittent exacerbations are a characteristic feature of the course of COPD. H. influenzae is the most common bacterial cause of exacerbations of COPD. Acquisition of new strains to which the patient lacks prior immunity is the primary mechanism that drives bacterial exacerbations.
Protection against invasive infection by Hib strains is mediated by serum bactericidal and opsonizing antibody to the type b capsular polysaccharide.

What are the clinical manifestations of infection with this organism?

Clinical manifestations of nontypeable H. influenzae

Otitis media. Nontypeable H. influenzae accounts for 25-35% of otitis media in children. The typical clinical presentation of acute otitis media in infants is fever and irritability, whereas older children often present with ear pain. Otitis media caused by nontypeable H. influenzae is less likely to cause fever and is less often associated with otorrhea than pneumococcal otitis media. Features associated with H. influenzae otitis media include a history of recurrent episodes, treatment failure, concomitant conjunctivitis, previous amoxicillin treatment, and bilateral otitis media.

Exacerbations of COPD. The course of COPD is characterized by intermittent exacerbations of the disease that result in lost work time, office and clinic visits, emergency room visits, hospital admissions, respiratory failure, and death. Approximately one-half of exacerbations are caused by bacteria with nontypeable H. influenzae being the most common bacterial cause. The three cardinal clinical manifestations of exacerbation include increased sputum volume, increased sputum purulence (color), and increased dyspnea compared to baseline symptoms.

Community acquired pneumonia. Nontypeable H. influenzae is an important cause of community acquired pneumonia, especially in the elderly and adults with COPD. Clinical features are similar to those of pneumonia caused by other bacteria and include fever, cough, and purulent sputum usually of several days duration.

Sinusitis. Nontypeable H. influenzae is a common cause of maxillary sinusitis in adults and children. Patients experience purulent nasal discharge, headache, and facial pain.

Bacteremia and invasive infections. Most invasive infections caused by H. influenzae in countries in which type b conjugate vaccines are used widely are caused by nontypeable strains. Most people with bacteremia have an underlying condition, such as alcoholism, cardiopulmonary disease, HIV infection, or cancer.

Neonatal and maternal sepsis. Neonatal sepsis caused by nontypeable H. influenzae is being recognized with increasing frequency. Many strains that cause neonatal sepsis are biotype IV and share many genotypic and phenotypic features with one another. Invasive biotype IV clonal strains are closely related to H. haemolyticus.

Clinical manifestations of H. influenzae type b.

Most infections caused by H. infuenzae type b strains occur in unimmunized or incompletely immunized children.

Meningitis. Meningitis is the most common and most serious manifestation of H. influenzae type b infection. Clinical features are indistinguishable from acute meningitis caused by other bacterial pathogens. The most common signs are fever and altered central nervous system (CNS) function. Nuchal rigidity suggests meningitis. The young child may show few specific signs, and nuchal rigidity is often absent.

Epiglottitis. Acute upper airway obstruction caused by cellulitis of the supraglottic tissues is a potentially lethal disease. The peak age incidence of epiglottitis is 2-7 years of age, but occurrence in adults is well known. The onset is often sudden with sore throat, fever, dyspnea progressing to dysphagia, pooling of oral secretions, and drooling. The child is restless, anxious, and often adopts a sitting position with neck extended and chin protruding to minimize airway obstruction. The epiglottis is red and swollen. Examination of the larynx should be performed only in a setting in which an airway can be placed, because examination, if injudiciously performed, may exacerbate airway obstruction.

Pneumonia and empyema. The true frequency of pneumonia caused by H. influenzae type b is difficult to determine with accuracy. The peak age incidence appears to be 4 months to 4 years of age. Children present with typical features of pneumonia. In the case of H. influenzae type b, the onset may be more insidious compared to the pneumococcus and Staphylococcus aureus.

Bacteremia without localized disease. H. influenzae type b may cause bacteremia without an obvious focus of infection, most commonly in children 6 months to 3 years of age. Fever, anorexia, and lethargy prompt a visit to a physician, and examination is unrevealing. High fever and leukocytosis are typical. Early diagnosis and therapy are important because patients may worsen rapidly.

Cellulitis. Predominantly seen in young children, cellulitis is manifested by fever and a raised, warm, tender area with a distinctive reddish blue hue, most often located on the cheek or periorbital region. Cellulitis may progress rapidly, and accompanying bacteremia is common. Septic arthritis. H. influenzae type b causes septic arthritis most often in a single large weight-bearing joint in children under age 2 years. The involved joint displays decreased mobility, pain on movement and swelling. The presentation can sometimes be more subtle with prolonged fever and irritability and few localizing symptoms.

What common complications are associated with infection with this pathogen?

Recurrent and chronic otitis media causes prolonged middle ear effusions, which leads to conductive hearing loss. Prolonged middle ear effusions may lead to delays in speech and language development because of muffled hearing at a critical time in development.
Exacerbations of COPD due to nontypeable H. influenzae in adults with advanced compromise in lung function can cause respiratory failure, which may require mechanical ventilation.
Neonatal sepsis due to invasive biotype IV strains of nontypeable H. influenzae is associated with a 50% mortality overall and a 90% mortality in premature infants.
Bacteremia with nontypeable H. influenzae in adults is a serious infection that can cause physiologic consequences of systemic sepsis and is associated with a variable mortality.
Subdural effusions are a common complication of H. influenzae type b meningitis. Clinical suspicion should be greatest when, after 2 or 3 days of adequate antibiotic therapy, there is a tense anterior fontanelle, seizures, or neurological deterioration.
The overall mortality rate of H. influenzae type b meningitis is less than 5%, but permanent neurological sequelae occur in many children following recovery. The most common sequela is hearing loss, but other more severe neurological deficits may be seen as well.
A potentially fatal complication of epiglotitis is upper airway obstruction.

How should I identify the organism?

Haemophilus influenzae is a small, non-motile, non-spore-forming gram-negative coccobacillus isolated exclusively from humans. No other natural host is known. It is recovered from the respiratory tract and, rarely, the genital tract.

By microscopy, H. influenzae is a small (1 x 0.3µ) gram-negative coccobacillus. It often stains faintly in clinical samples and may, thus, be overlooked, particularly in sputum samples.
The organism grows well on chocolate agar. Many strains grow best in 5-10% carbon dioxide. Colonies grow to 0.5-0.8 mm after overnight growth. Colonies of nontypeable (non-encapsulated) strains are usually granular, transparent, circular, and dome-shaped. Colonies of encapsulated strains have a mucoid appearance.
H. influenzae is identified in the clinical microbiology laboratory based on its growth requirement for hemin (called X factor) and nicotinamide adenine dinucleotide (called Y factor). Encapsulated strains are identified by reactivity with capsule-specific antisera.
Strains of H. haemolyticus are frequently misidentified as H. influenzae in clinical microbiology laboratories and in published studies. This confusion occurs because many strains of H. haemolyticus are non-haemolytic. Haemolysis is the sole characteristic used to distinguish H. haemolyticus from H. influenzae in commercial kits and in currently accepted methods used in clinical microbiology laboratories worldwide. Accurate identification of Haemophilus species is important, because H. influenzae is a potential pathogen and H. haemolyticus is a commensal. Strains of H. haemolyticus and H. influenzae can be distinguished by using polymerase chain reaction (PCR) based on 16S ribosomal DNA sequences or by sequence differences in outer membrane protein P6 or by differences in superoxide dismutase. A convenient method that can be used widely in clinical laboratories is urgently needed.
The diagnosis of invasive H. influenzae type b infections is generally established by culture of the organism in normally sterile body fluids, including cerebrospinal fluid, blood, and other normally sterile sites. Detection of capsular antigen in serum, cerebrospinal fluid, or concentrated urine may be used for diagnosis as well.

How does this organism cause disease?

Nontypeable strains cause otitis media by contiguous spread from the nasopharynx to the middle ear space by the Eustachian tube.
Exacerbations of COPD result from the acquisition of new pathogens, including nontypeable H. influenzae.
Strains of nontypeable H. influenzae show differences in their pathogenic potential. A subset of strains that colonize the nasopharynx is capable of causing otitis media. Strains that cause exacerbations of COPD contain different sets of genes compared to strains that cause otitis media.
H. influenzae expresses multiple adhesions, each with different binding specificities to host molecules.
H. influenzae biofilms are present in the middle ears of children with chronic and recurrent otitis media. Biofilms are more resistant to host clearance mechanisms and more resistant to antibiotics than planktonic bacteria.
The polyribitol ribose phosphate (PRP) capsule is the critical virulence factor for type b strains, facilitating invasion of the bloodstream and spread of infection by the hematogenous route.

WHAT’S THE EVIDENCE for specific management and treatment recommendations?

“Diagnosis and Management of Acute Otitis Media”. (Nontypeable H. influenzae is one of three bacterial pathogens that cause otitis media along with S. pneumoniae and M. catarrhalis. An etiologic diagnosis requires tympanocentesis, an invasive procedure not performed routinely in clinical practice. Therefore, treatment of otitis media is empirical. Clinicians are advised to follow the guidelines of the American Academy of Pediatrics.)

“Advisory Committee on Immunization Practices (ACIP)”. (All children should be immunized with a conjugate vaccine beginning at age 2 months. Clinicians should consult the uniform guidelines that have been endorsed by the Advisory Committee on Immunization Practices, the American Academy of Pediatrics and the American Academy of Family Physicians.)

“Current Trends Prevention of Secondary Cases of Haemophilus influenzae Type b Disease*”. (Children and adults [except pregnant women] in households with one incompletely immunized contact <4 years old should receive oral rifampin prophylaxis. Clinicians should refer to the Centers for Disease Control and textbooks of medicine for details.)

Mills, N, Best, EJ, Murdoch, D, Souter, M. “What is behind the ear drum? The microbiology of otitis media and the nasopharyngeal flora in children in the era of pneumococcal vaccination”. J Paediatr Child Health. vol. 51. 2015 Mar. pp. 300-6.

Murphy, TF., Longo, DL, Fauci, AS, Kasper, DL, Hauser, SL, Jameson, JL, Loscalzo, J. ” and infections”. Harrison's principles of Internal Medicine. 2012. pp. 1228-33. (The preferred therapy for H. influenzae type b meningitis is intravenous cephalosporin such as ceftriaxone of cefotaxime. Readers are referred to textbooks of medicine for detailed recommendations.)

Murphy, TF.. “Nontypeable Haemophilus influenzae: the future is now”. Clin Vaccine Immunol. vol. 22. 2015 May. pp. 459-66.

Sethi, S, Murphy, TF.. “Infection in the pathogenesis and course of chronic obstructive pulmonary disease”. N Engl J Med. vol. 359. 2008. pp. 2355-65. (Antimicrobial therapy of exacerbations of COPD is generally empirical with agents that are active against H. influenzae in addition to M. catarrhalis and S. pneumoniae. Patients experiencing moderately severe and severe exacerbations appear to benefit from antimicrobial therapy. The main benefits are more rapid recovery and reduced likelihood of complications. Clinicians are referred to a treatment algorithm in this article, which is based on recommendations of experts.)

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