Population-based study of non-typable Haemophilus influenzae invasive disease in children and neonates

doi:10.1016/0140-6736(93)93059-A

The Lancet

Volume 341, Issue 8849, 3 April 1993, Pages 851-854

https://doi.org/10.1016/0140-6736(93)93059-A Get rights and content

Abstract

The extent of non-capsulate, non-serotypable Haemophilus influenzae (NST) as a cause of serious invasive disease in children has not been fully defined. We describe the epidemiology of these childhood infections from cases identified during a continuing prospective survey of invasive H influenzae disease in the Oxford region, UK. 408 strains of H influenzae were isolated from cases of invasive disease. 383 (94%) were H influenzae type b (Hib), 24 (6%) were NST strains, and 1 was a type f strain. 3 of the NST strains were non-capsulate type b mutants (b-), but the remaining 21 strains were from the phylogenetically distinct and heterogeneous population of non-capsulate H influenzae (NC). 10 of the NC strains were isolated from neonates with sepsis; crude mortality rate was 40%, with an incidence of 4·6 cases per 100000 livebirths. 11 NC strains were isolated from children after the neonatal period and under 10 years of age, 4 (36%) of which had severe, unrelated, predisposing conditions. The incidence of NC invasive diseases in these children was 0·5 per 100 000 per year. The attributable mortality for these infections was 10%.

Infections due to these H influenzae strains are, after the implementation of Hib vaccines, likely to persist and represent a substantial proportion of the serious infections caused by this species.

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Cited by (99)

Non-typeable Haemophilus influenzae, an under-recognised pathogen
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As with many other bacterial infections, the highest incidence of invasive NTHi disease occurs at the extremes of age. Neonatal NTHi infections are well described, with an incidence of 1·6–4·9 per 1000 livebirths55–57 and account for about 5% of all neonatal invasive bacterial infections.55,56 The infection develops rapidly (usually within 24 h of birth) and follows a fulminant course with a high case fatality, particularly in premature infants.
Non-typeable Haemophilus influenzae (NTHi) is a major cause of mucosal infections such as otitis media, sinusitis, conjunctivitis, and exacerbations of chronic obstructive pulmonary disease. In some regions, a strong causal relation links this pathogen with infections of the lower respiratory tract. In the past 20 years, a steady but constant increase has occurred in invasive NTHi worldwide, with perinatal infants, young children, and elderly people most at risk. Individuals with underlying comorbidities are most susceptible and infection is associated with high mortality. β-lactamase production is the predominant mechanism of resistance. However, the emergence and spread of β-lactamase-negative ampicillin-resistant strains in many regions of the world is of substantial concern, potentially necessitating changes to antibiotic treatment guidelines for community-acquired infections of the upper and lower respiratory tract and potentially increasing morbidity associated with invasive NTHi infections. Standardised surveillance protocols and typing methodologies to monitor this emerging pathogen should be implemented. International scientific organisations need to raise the profile of NTHi and to document the pathobiology of this microbe.
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Evolving epidemiology of invasive Haemophilus infections in the post-vaccination era: Results from a long-term population-based study
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Hif infections are similar to NTHi in that 10/14 (72%) cases had severe predisposing conditions and the most common clinical diagnosis was pneumonia. Other studies have reported a high prevalence (60–80%) of predisposing conditions among patients with Hif infections [12,23] and they are most frequent in young individuals and the elderly [4,23]. Resman et al. [24] recently reported a significant increase in serious invasive infections ascribed to Hif, mainly in individuals >60 years of age in Sweden.
Historically, Haemophilus influenzae (Hi) serotype b (Hib) caused most invasive Haemophilus infections worldwide, mainly in children. In 1989 routine childhood vaccination against Hib was initiated in Iceland. We conducted a population-based study of all patients in the country with Haemophilus spp. isolated from sterile sites (n = 202), from 1983 to 2008. Epidemiology, clinical characteristics of the infections and serotypes of the isolates were compared during the pre-vaccination (1983–1989) and post-vaccination era (1990–2008). Following the vaccination, the overall incidence of Hib decreased from 6.4 to 0.3/100 000 per year (p <0.05) whereas the incidence did not change significantly for infections caused by Haemophilus sensu lato not serotype b, hereafter referred to as non-type b Hi (0.9 vs 1.2, respectively). The most frequent diagnosis prior to 1990 was meningitis caused by Hib, which was subsequently replaced by pneumonia and bacteraemia caused by non-type b Hi. Most commonly, non-type b Hi were non-typeable (NTHi; 40/59), followed by Hi serotype f (14/59) and Hi serotype a (3/59). Pregnancy was associated with a markedly increased susceptibility to invasive Haemophilus infections (RR 25.7; 95% CI 8.0–95.9, p <0.0001) compared with non-pregnant women. The case fatality rate for Hib was 2.4% but 14% for non-type b Hi, highest at the extremes of age. Hib vaccination gives young children excellent protection and decreases incidence in the elderly due to herd effect in the community. Replacement with other species or serotypes has not been noted. Pregnant women are an overlooked risk group.
Invasive disease caused by Haemophilus influenzae in Sweden 1997-2009; evidence of increasing incidence and clinical burden of non-type b strains
2011, Clinical Microbiology and Infection
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Invasive NTHi cases are suggested to be opportunistic infections [3], even though information on correlated medical conditions is scarce. Invasive disease by H. influenzae has historically been analogous with disease by encapsulated strain type b (Hib), a feared cause of sepsis, epiglottitis and meningitis in children and occasionally in adults [5]. In the early 1990s, the conjugated Hib vaccine was introduced in most countries in the Western World, and a dramatically reduced incidence of invasive Hib disease occurred [6].
Introduction of a conjugated vaccine against encapsulated Haemophilus influenzae type b (Hib) has led to a dramatic reduction of invasive Hib disease. However, an increasing incidence of invasive disease by H. influenzae non-type b has recently been reported. Non-type b strains have been suggested to be opportunists in an invasive context, but information on clinical consequences and related medical conditions is scarce. In this retrospective study, all H. influenzae isolates (n = 410) from blood and cerebrospinal fluid in three metropolitan Swedish regions between 1997 and 2009 from a population of approximately 3 million individuals were identified. All available isolates were serotyped by PCR (n = 250). We observed a statistically significant increase in the incidence of invasive H. influenzae disease, ascribed to non-typeable H. influenzae (NTHi) and encapsulated strains type f (Hif) in mainly individuals >60 years of age. The medical reports from a subset of 136 cases of invasive Haemophilus disease revealed that 48% of invasive NTHi cases and 59% of invasive Hif cases, respectively, met the criteria of severe sepsis or septic shock according to the ACCP/SCCM classification of sepsis grading. Onefifth of invasive NTHi cases and more than one-third of invasive Hif cases were admitted to intensive care units. Only 37% of patients with invasive non-type b disease had evidence of immunocompromise, of which conditions related to impaired humoral immunity was the most common. The clinical burden of invasive non-type b H. influenzae disease, measured as days of hospitalization/100 000 individuals at risk and year, increased significantly throughout the study period.
Meningitis and septicemia caused by nontypeable Haemophilus influenzae in a previously healthy 2-year-old girl
2011, Journal of Infection and Chemotherapy
Nontypeable Haemophilus influenzae (NTHi) commonly colonizes the upper respiratory tract of children and causes otitis media, sinusitis, and bronchitis. Invasive NTHi diseases such as meningitis and septicemia have rarely been reported, especially in children with underlying predisposing conditions such as head trauma and immune compromise. However, we report a previously healthy 2-year-old girl who developed meningitis and septicemia caused by NTHi biotype ΙΙΙ. She was treated with dexamethasone, meropenem, and ceftriaxone, and recovered uneventfully. We wish to emphasize that NTHi should be borne in mind as a potential pathogen that can cause meningitis and septicemia, even in previously healthy children.
Invasive Haemophilus influenzae in British Columbia: Non-Hib and non-typeable strains causing disease in children and adults
2011, International Journal of Infectious Diseases
Citation Excerpt :
In Canada, a historic low in the number of invasive Hib disease was recorded as early as 2000 (with only four cases found by a network of 12 major pediatric centers across the country), eight to nine years after the Hib conjugate vaccine was introduced.6 Before Hib conjugate vaccines were widely used, non-Hib H. influenzae (either non-encapsulated strains or other serotypes) were not regarded as significant causes of invasive disease.2,3,7 In theory, vaccines that target only one serotype may drive the organism to either switch and/or replace their capsules with non-vaccine capsular types or shed their capsule altogether to become resistant to the vaccine.8–10
To characterize invasive Haemophilus influenzae and to examine the population at risk for invasive H. influenzae disease in British Columbia, Canada, 2008–2009.
H. influenzae recovered from individual patients were characterized by serotyping, biotyping, multilocus sequence typing (MLST), and antibiotic susceptibility testing. Age information was recorded from specimen requisition forms.
Of the 98 cases, 66% were caused by non-typeable strains, followed by serotypes b (12%), a (10%), f (10%), and e (1%). Cases caused by serotypes b and f and non-typeable strains were mainly in adults over 18 years of age, while cases due to serotype a were mainly in children under the age of 2 years. Different sequence types were found in encapsulated strains according to their serotypes, and non-typeable strains had their own unique sequence types. No capsule switching was documented. Antibiotic resistance was common among non-typeable strains, with 31% identified as genotypic β-lactamase-negative ampicillin-resistant (BLNAR) strains.
Invasive H. influenzae disease in a population vaccinated against Hib was age-dependent and involved both non-typeable and encapsulated strains. Adults were susceptible to invasive diseases due to non-typeable and serotype b and f strains, while in children, most diseases were due to serotype a bacteria.

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ARTICLESPopulation-based study of non-typable Haemophilus influenzae invasive disease in children and neonates

Abstract

Lancet

Mol Cell Probes

FEMS Microbiol Letts

Meningitis caused by nontypable Haemophilus influenzae in a four months old infant

Ped Infect Dis

Nontypable Haemophilus influenzae: a review of clinical aspects, surface antigens, and the human immune response to infection

Rev Infect Dis

Clonal Analysis of Haemophilus influenzae isolated from children from Pakistan with lower respiratory tract infections

J Infect Dis

Nontypable Haemophilus influenzae (biotype 4) as a neonatal, maternal and genital pathogen

Rev Infect Dis

Characteristic features of neonatal sepsis due to Haemophilus influenzae.

Rev Infect Dis

Finnish efficacy trials with Haemophilus influenzae type b vaccines

J Infect Dis

Prevention of Haemophilus type b infections in Apache and Navajo Children

J Infect Dis

Genetics of spontaneous, high frequency loss of capsule expression in Haemophilus influenzae.

Infect Immun

A subtyping system for nontypable Haemophilus influenzae based on outer-membrane proteins

J Infect Dis

Characterization of non-capsulate Haemophilus influenzae by whole-cell polypeptide profiles, restriction endonucleases analysis and rRNA gene restriction patterns

J Clin Microbiol

ARTICLES
Population-based study of non-typable Haemophilus influenzae invasive disease in children and neonates