Haemophilus influenzaeA49.2

The name haemophilus is based on the particular preference of the bacteria for culture media with blood or haemoglobin supplements. The misleading name "influenza" goes back to Richard Pfeiffer, an assistant of R.Koch, who in 1892 believed to have discovered the causative agent of influenza.

Haemophilus influenzae, a species of the genus Haemophilus in the family Pasteurellaceae, is an immotile, Gram-negative, coccoid rod bacterium. Haemophilus influenzae bacteria can occur as encapsulated ("typeable") or unencapsulated strains ("non-typeable" or NTHi). The only known reservoir of the pathogen is humans. The bacteria colonize the upper respiratory tract up to 50% in adults and up to 75% in children without causing symptoms. Vaginal colonization is also possible.

Important classification criteria for individual Haemophilis species are the biochemical structure of the capsular polysaccharides.

Haemophilus influenza is differentiated into eight biotypes based on various biochemical characteristics:

Haemophilus influenza type I to type VIII).

Some Haemophilus influenzae strains form a capsule. In encapsulated Haemophilus species, further serovars are differentiated according to the biochemical structure of the capsular polysaccharides (a to f). The most important is Haemophilus influenza type b (Hib), which is responsible for about 95% of severe Haemophilus infections in children. Encapsulated, H. influenzae is obligate pathogen. However, Haemophilus influenza type b has become very rare since the introduction of Haemophilus vaccination. The unencapsulated bacterial variant belongs to the normal flora of humans. It accounts for about 1.8% of the total human flora in children and 0.15% in adults. This variant only becomes pathogenic under certain circumstances (e.g. epithelial damage caused by nicotine). Since H. influenzae can absorb DNA from the environment, both encapsulated strains can lose their capsule and unencapsulated strains can acquire the ability to form capsules.

Before the development of the Hib conjugate vaccine in the late 1980s, Haemophilus type b (Hib) was the leading cause of bacterial meningitis in young children worldwide. In 2000 - before the widespread introduction of vaccination in resource-poor countries - 8.13 million children under 5 years of age worldwide contracted severe Hib, and 371,000 children died from Hib infection, according to a WHO estimate. In 2013, 95% of WHO Member States (corresponding to 81% of children born in 2012) had included Hib vaccination in their immunization calendar, resulting in a reduction of up to 90% of invasive Hib cases in these countries. In Europe, as in several other regions, NTHi is now the most common invasive Hi type. In unvaccinated populations, however, Hib is still the leading cause of non-epidemic bacterial meningitis in children under 12 months of age.

Hi diseases occur worldwide. In Germany, invasive Hi diseases are among the rather rare notifiable diseases with a nationwide incidence of up to 1.0/100,000 inhabitants. Elderly people are most frequently affected. In addition, infants and small children < 5 years of age are also affected. The majority of illnesses are predominantly caused by NTHi in all age groups (Jalalvand F et al. 2014). Invasive infections caused by Hib, on the other hand, are rather rare in Germany, with approximately 10-35 cases per year. Current case figures on invasive infections caused by Hi and other epidemiological parameters can be found in the current Infection Epidemiology Yearbook at www.rki.de/jahrbuch.

The mechanisms of pathogenicity are still unclear. Invasiveness is favored when epithelial damage is present. In this case, the bacteria can apparently find their way between the epithelial cells into the submucosa. One of the most important pathogenicity criteria is capsule. Apparently, increased resistance to phagocytosis is mediated by the capsule, which increases its pathogenicity (Rao VK et al.1999). Furthermore, IgA proteases are produced, reducing the local immune response (by cleavage of immunoglobulin) against H. influenzae (Jalalvand F et al.2014).

Route of infection: Transmission is by droplet infection. Incubation period: The incubation period is not precisely known, possibly 2 to 4 days.

Haemophilus influenza (Hi) often causes respiratory infections (sinusitis, bronchitis), especially in patients with pre-existing lung disease. Other organs such as eyes (conjunctivitis), ears (otitis media) and vagina (vaginitis) may also be affected.

Penumonia: Invasive Hi disease most commonly presents as pneumonia (often associated with bacteremia of the causative organism).

Epiglottitis: Epiglottitis is also feared, especially in children. This develops within a few hours; 25-50% of patients present with catarrhal symptoms, dysphagia, inspiratory stridor, and agitation. This is followed by rapid onset of shock symptoms with cyanosis and high fever.

Meningitis: Meningitis caused by Hi often has a fulminant onset with sudden onset of fever, vomiting, lethargy and meningeal irritation. The lethality is about 5% in industrialized countries. There is also a high risk of sequelae: up to 25% develop permanent hearing loss or other long-term neurological damage.

Other: Rarely, septic arthritis, phlegmon, osteomyelitis, peritonitis, empyema, or pericarditis occur in the setting of invasive disease.

Pregnant women are at significantly increased risk for invasive NTHi infections. Infection can lead to sepsis in the mother, plus subsequent pregnancy complications including premature birth or miscarriage.

Duration of infectiousness: Infectiousness exists as long as Hi-bacteria are detectable, i.e. possibly beyond the end of symptoms. Patients are no longer infectious 24 h after the start of effective antibiotic therapy. In Hib, the administration of rifampicin leads to germ adication in the patient's nasopharynx.

Culture: Bacteria of the genus Haemophilus require certain growth factors from the blood. H. influenzae requires both factorX and factor V.

Hi disease cannot be distinguished clinically from invasive disease caused by other bacteria. Therefore, if Hi infection is clinically suspected, rapid diagnostic workup and therapy should be initiated.

Laboratory: The investigation for Hi is basically based on the cultivation, identification and typing of the pathogen from patient samples. Culture-independent methods include direct microscopy of cerebrospinal fluid and detection by polymerase chain reaction (PCR). In addition, antigen detections for CSF diagnostics are commercially available.

Diagnostic samples should always be collected before starting antibiotic therapy. Hi is a fastidious growing bacterium and a culture should therefore be established as soon as possible, ideally within 2-4 h of sample collection. In the case of equivocal isolates, PCR detection of specific Hi genes can confirm the diagnosis. Mass spectrometric identification (MALDI-TOF) is also a suitable diagnostic method.

Molecular biological detection numerous realtime PCRs are established which detect specific hi-genes. Unencapsulated strains (these cause by far the most invasive infections) are not detected by these tests.

Rapid test: Rapid tests using latex agglutination are available for the direct detection of Hi antigens from body fluids, especially cerebrospinal fluid. However, for the detection of Hi, these tests offer no advantage over direct microscopy of CSF for clinical decision making in suspected meningitis, among other reasons, due to limited sensitivity and specificity.

Antibody detection against Hib is used to determine the immunity status before or after vaccination. Antibody determination is not suitable for the diagnosis of an acute infection.

The typing of Hi strains is based on the examination of the capsule of cultivated isolates. For special epidemiological questions, e.g. for the elucidation of a possible disease transmission, Hi strains can be fine-typed by multilocus sequence typing (MLST) or genome sequencing.

The agents of choice for invasive Hi diseases are group 3 cephalosporins for parenteral therapy (e.g. cefotaxime and ceftriaxone). Because of the presence of ampicillin-resistant strains, ampicillin should be used only when Hi bacterial sensitivity has been demonstrated. In Hib meningitis, administration of dexamethasone before or together with the first antibiotic dose may counteract cerebral edema.

Furthermore, in invasive Hib disease, administration of rifampicin prior to discharge is recommended to eradicate colonization of the nasopharynx and prevent secondary disease in the patient or subsequent cases in the community. This is particularly important if the patient has not been treated with cefotaxime or ceftriaxone.

Prophylaxis: see below for infection control and hygiene measures. Haemophilus influenza infection control and hygiene measures

Prophylaxis: A vaccination against Haemophilus influenzae exists against Hi caps type b (Hib). This is recommended in Germany since 1990 as a standard vaccination in infancy and early childhood.

1. Deeming JE (1955) Haemophilus influenzae vaginitis. Northwest Med 54:992-993.
2. Gozum GG et al.(2020) Case report: Invasive non-type b Haemophilus influenzae in immunocompromised children. Am J Case Rep 21:e920853.
3. Jalalvand F et al.(2014) Haemophilus influenzae: recent advances in the understanding of molecular pathogenesis and polymicrobial infections. Curr Opin Infect Dis 27:268-274.
4. Poje G et al (2003) General methods for culturing Haemophilus influenzae. Methods Mol Med 71:51-56.
5. Rao VK et al.(1999) Molecular determinants of the pathogenesis of disease due to non-typable Haemophilus influenzae. FEMS Microbiol Rev 23:99-129.
6. Shooraj F et al. (2019) Clonal diversity of Haemophilus influenzae carriage isolated from under the age of 6 years children. BMC Res Notes 12:565.
7. St Geme JW 3rd (2000) The pathogenesis of nontypable Haemophilus influenzae otitis media. Vaccine 19 Suppl 1:S41-50.
8. St Geme JW 3rd (1997) Insights into the mechanism of respiratory tract colonization by nontypable Haemophilus influenzae. Pediatr Infect Dis J 16:931-935.