Invasive disease caused by Haemophilus influenzae in Sweden 1997–2009; evidence of increasing incidence and clinical burden of non-type b strains

Abstract

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. One-fifth 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.

Adhesin genes and serum resistance in Haemophilus influenzae type f isolates

“…In the post-Hib vaccine era, invasive disease in children due to H. influenzae is uncommon, with the majority of these infections due to unencapsulated strains, with the remainder being non-b encapsulated strains, predominantly serotypes f and a in North America and serotypes f and e in Europe (Tsang et al, 2006;Adam et al, 2010;Ladhani et al, 2010Ladhani et al, , 2012Agrawal & Murphy, 2011;Resman et al, 2011a;Rubach et al, 2011). To understand better the ability of serotype f strains to produce invasive infection, we assembled a panel of Hif isolates from a diversity of clinical sources for factors related to pathogenesis.…”

“…Given the reduction in Hib carriage among Hib conjugate vaccine recipients, concern exists as to whether invasive disease due to Hif or other non-b encapsulated strains will become more prevalent due to serotype replacement (Takala et al, 1991;Urwin et al, 1996;Ward, 1996;Tsang, 2007). In fact, several investigations in North America and Europe in the post-conjugate vaccine era have indicated an increased incidence, albeit small, of invasive infections due to non-b H. influenzae, with a predominance of nontypable and Hif strains, primarily in older age groups (Urwin et al, 1996;Ladhani et al, 2010Ladhani et al, , 2012MacNeil et al, 2011;Resman et al, 2011a;Rubach et al, 2011;Ladhani, 2012).…”

“…(Takala et al, 1991;Urwin et al, 1996;Ward, 1996;Tsang, 2007). In fact, several investigations in North America and Europe in the post-conjugate vaccine era have indicated an increased incidence, albeit small, of invasive infections due to non-b H. influenzae, with a predominance of nontypable and Hif strains, primarily in older age groups (Urwin et al, 1996;Ladhani et al, 2010Ladhani et al, , 2012MacNeil et al, 2011;Resman et al, 2011a; Rubach et al, 2011;Ladhani, 2012).Invasive disease associated with Hif appears to disproportionately affect individuals with underlying co-morbidities, including adults suffering from chronic obstructive pulmonary disease (COPD), ethanol abuse, chronic renal disease and human immunodeficiency virus/AIDS, and children with immunoglobulin deficiencies, severe combined immunodeficiency, human immunodeficiency virus/ AIDS, malignancy and sickle-cell disease (Nitta et al, 1995;Urwin et al, 1996;Fickweiler et al, 2004;Resman et al, 2011b;Watson et al, 2011). This is in contrast to Hib, which is considered a primary pathogen able to cause disease in otherwise healthy and immunocompetent individuals, predominantly children (Morris et al, 2008 (St Geme et al, 1993, 1996Mhlanga-Mutangadura et al, 1998), PCR analysis of variability at a lipo-oligosaccharide (LOS) biosynthetic island, and assessment of their ability to resist the bactericidal activity of adult normal human serum (NHS).…”

Haemophilus influenzae stores and distributes hemin by using Protein E

“…After introduction of a vaccine against H. influenzae type b (Hib) in the 1990s, NTHi are now responsible for the majority of Haemophilus infections (Murphy, 2003). NTHi colonizes the mucosa and causes respiratory tract infections such as acute otitis media in children and exacerbations in patients with chronic obstructive pulmonary disease (COPD), but in rare cases also invasive disease, mainly meningitis and sepsis (Murphy et al, 2009;Resman et al, 2011) H. influenzae has an absolute requirement for heme since it lacks 6 of 7 enzymes in the heme synthetic pathway that consequently leads to an inability to produce protoporphyrin IX (Loeb, 1995). The success of H. influenzae colonization thus depends on its ability to acquire protoporphyrin IX or heme from the host (Infante-Rivard and Fernandez, 1993).…”

Identification of a Haemophilus influenzae Factor H–Binding Lipoprotein Involved in Serum Resistance

“…In contrast, NTHi are often associated with acute otitis media, sinusitis and are responsible for exacerbations in patients suffering from chronic obstructive pulmonary disease or cystic fibrosis (2,5,6). After introduction of the Hib vaccine in the early 1990s, which has successfully abrogated Hib infections, the incidence of other non-Hib H. influenzae, in particular NTHi and serotype f (Hif), has steadily increased as reported in several countries of the Western world (7)(8)(9).…”