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Invasive disease by Haemophilus influenzae in Sweden in the era of the H. influenzae type b vaccine

Resman, Fredrik LU (2012) In Lund University, Faculty of Medicine Doctoral Dissertation Series 2012:70.
Abstract (Swedish)
Popular Abstract in Swedish

Populärvetenskaplig svensk sammanfattning

Har allvarliga infektioner orsakade av bakterien Haemophilus influenzae försvunnit? En undertyp av H. influenzae, typ b (Hib), var tidigare en fruktad orsak till struplocksinflammation, hjärnhinneinflammation och svår blodförgiftning hos små barn. Problemet var så stort att allmän vaccination mot Hib infördes i många länder i början av 1990-talet, bland annat i Sverige. Efter detta har infektioner med Hib nästan försvunnit, och den inledande frågan är därför berättigad. Under de senaste 15 åren har flera internationella rapporter gjort gällande att antalet allvarliga infektioner med H. influenzae är på väg att öka igen, men nu orsakat av andra... (More)
Popular Abstract in Swedish

Populärvetenskaplig svensk sammanfattning

Har allvarliga infektioner orsakade av bakterien Haemophilus influenzae försvunnit? En undertyp av H. influenzae, typ b (Hib), var tidigare en fruktad orsak till struplocksinflammation, hjärnhinneinflammation och svår blodförgiftning hos små barn. Problemet var så stort att allmän vaccination mot Hib infördes i många länder i början av 1990-talet, bland annat i Sverige. Efter detta har infektioner med Hib nästan försvunnit, och den inledande frågan är därför berättigad. Under de senaste 15 åren har flera internationella rapporter gjort gällande att antalet allvarliga infektioner med H. influenzae är på väg att öka igen, men nu orsakat av andra typer än just typ b som vaccinationen är riktad mot.

Det huvudsakliga syftet med detta arbete var att ta reda på om antalet allvarliga infektioner (blodförgiftningar eller hjärnhinneinflammationer) orsakade av H. influenzae ökat i Sverige sedan mitten av 1990-talet, vilka bakterieisolat som orsakat dessa infektioner, och vad som kännetecknar de patienter som drabbades. Samtidigt undersöktes utvecklingen av antibiotikaresistens hos de bakteriestammar som orsakar allvarliga infektioner. I laboratoriet undersöktes dessutom två faktorer hos bakterierna som kan bidra till att infektioner blir allvarliga; förmågan att fästa sig fast vid komponenter i den bindväv som finns under slemhinnan i luftvägen, och förmågan att avstyra hotet från människans komplementsystem.

Våra resultat visar att det har skett en ökning av allvarliga infektioner orsakade av H. influenzae i Sverige sedan 1997, men att denna ökning har drabbat företrädelsevis äldre vuxna. Hos små barn syns ingen ökning, och den farligaste varianten av bakterien, typ b, är fortsatt mycket ovanlig. Ökningen orsakades istället av bakterieisolat som saknar kolhydrathölje och som därför är otypbara, samt av isolat av typ f. Vi kunde konstatera att de infektioner som drabbade friska vuxna ofta blev mycket allvarliga. Vi identifierade samtidigt en ökande resistens (motståndskraft) mot den vanligast använda gruppen av antibiotika, β-laktamantibioika.

Undersökningar i laboratoriet visade att H. influenzae kan binda till bindväven som ligger under slemhinnan i luftvägen genom ett ytprotein, Protein E. Denna förmåga bidrar troligen till bakteriens möjlighet att lämna slemhinnan och orsaka djupare, mer allvarliga infektioner. Vi visste sedan tidigare att H. influenzae binder komplementreglerproteiner för att undvika att bli själv bli offer för komplementsystemet. Vi kunde dock inte hitta någon skillnad i inbindningen till komplementreglerproteiner mellan bakterier som orsakat blodförgiftning och bakterier som orsakat sjukdom i luftvägen.

Sammantaget visar resultaten att vaccination mot Hib fortsatt mycket framgångsrikt förebygger allvarliga infektioner hos små barn, men att övervakningen av H. influenzae bör fortsätta. Bland gruppen icke typbara H. influenzae ökar både antalet allvarliga infektioner och andelen isolat med resistens mot antibiotika. (Less)
Abstract
What is the current status of Haemophilus influenzae as an agent of invasive infection in Sweden? H. influenzae type b (Hib) used to be a common cause of meningitis, epiglottitis and severe sepsis in young children. In the late 1980’s an effective conjugated vaccine against Hib was developed and a dramatic fall in Hib incidence was observed in countries that implemented vaccination. This includes Sweden, where the vaccine was implemented in 1992. Since the mid 1990’s, scattered international reports have suggested increasing incidences of invasive disease caused by non-type b isolates of H. influenzae. A few of these reports have suggested serotype replacement.

In order to answer the initial question, we studied the epidemiology,... (More)
What is the current status of Haemophilus influenzae as an agent of invasive infection in Sweden? H. influenzae type b (Hib) used to be a common cause of meningitis, epiglottitis and severe sepsis in young children. In the late 1980’s an effective conjugated vaccine against Hib was developed and a dramatic fall in Hib incidence was observed in countries that implemented vaccination. This includes Sweden, where the vaccine was implemented in 1992. Since the mid 1990’s, scattered international reports have suggested increasing incidences of invasive disease caused by non-type b isolates of H. influenzae. A few of these reports have suggested serotype replacement.

In order to answer the initial question, we studied the epidemiology, the clinical burden and antimicrobial resistance of invasive H. influenzae in Sweden 1997-2010. Two aspects of the pathogenesis of invasive H. influenzae disease were addressed; bacterial binding to the extracellular matrix and the role of complement regulator binding in invasive disease. A case report of a severe invasive H. influenzae type f infection, including an examination of contributing host factors, is also presented.

Our results suggest that invasive disease by H. influenzae has not disappeared, but the epidemiology has radically changed. We found no support for serotype replacement in young children. In adults, and especially elderly adults, the incidence of invasive disease by non-typeable H. influenzae (NTHi) increased significantly during the study period. The results also suggest an increased incidence of invasive disease by H. influenzae type f (Hif), and type f is the most common serotype in Sweden today. Cases of invasive disease by non-type b isolates that occurred in healthy adults were often severe, suggesting the existence of hypervirulent non-type b strains. The β-lactam resistance of invasive H. influenzae isolates increased during the study period, due to an increase of β-lactamase negative β-lactam resistant NTHi. A clonal expansion of a β-lactamase negative ampicillin resistant (BLNAR) clone, frequently found in invasive disease, was suggested.

The ability of H. influenzae to bind laminin, and anchor the extracellular matrix through the adhesin Protein E was confirmed. Binding to complement regulators was not higher in invasive as compared to nasopharyngeal NTHi isolates, and thus did not seem central for invasive capacity. Speculation, but no comprehensive conclusion as to what host factors relate to invasive disease by H. influenzae in adults was possible.

The results suggest that the vaccination against H. influenzae type b remains very effective 20 years after it was introduced, but that continued surveillance of incidence and antimicrobial resistance of invasive Haemophilus disease is warranted. The results also suggest that ongoing research should focus on non-typeable H. influenzae, which today dominates all types of H. influenzae infections. (Less)
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author
supervisor
opponent
  • Professor Olcén, Per, Örebro Universitet
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Haemophilus influenzae, sepsis, epidemiology, antimicrobial resistance, bacterial adhesion
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
volume
2012:70
pages
150 pages
publisher
Department of Laboratory Medicine, Lund University
defense location
CRCs Aula, Skånes Universitetssjukhus, Malmö
defense date
2012-09-07 13:00
ISSN
1652-8220
ISBN
978-91-87189-33-3
language
English
LU publication?
yes
id
89d877e9-96fa-492b-b7c8-b2c857763660 (old id 2971938)
date added to LUP
2012-08-17 10:00:55
date last changed
2016-09-19 08:44:48
@phdthesis{89d877e9-96fa-492b-b7c8-b2c857763660,
  abstract     = {What is the current status of Haemophilus influenzae as an agent of invasive infection in Sweden? H. influenzae type b (Hib) used to be a common cause of meningitis, epiglottitis and severe sepsis in young children. In the late 1980’s an effective conjugated vaccine against Hib was developed and a dramatic fall in Hib incidence was observed in countries that implemented vaccination. This includes Sweden, where the vaccine was implemented in 1992. Since the mid 1990’s, scattered international reports have suggested increasing incidences of invasive disease caused by non-type b isolates of H. influenzae. A few of these reports have suggested serotype replacement. <br/><br>
In order to answer the initial question, we studied the epidemiology, the clinical burden and antimicrobial resistance of invasive H. influenzae in Sweden 1997-2010. Two aspects of the pathogenesis of invasive H. influenzae disease were addressed; bacterial binding to the extracellular matrix and the role of complement regulator binding in invasive disease. A case report of a severe invasive H. influenzae type f infection, including an examination of contributing host factors, is also presented.<br/><br>
Our results suggest that invasive disease by H. influenzae has not disappeared, but the epidemiology has radically changed. We found no support for serotype replacement in young children. In adults, and especially elderly adults, the incidence of invasive disease by non-typeable H. influenzae (NTHi) increased significantly during the study period. The results also suggest an increased incidence of invasive disease by H. influenzae type f (Hif), and type f is the most common serotype in Sweden today. Cases of invasive disease by non-type b isolates that occurred in healthy adults were often severe, suggesting the existence of hypervirulent non-type b strains. The β-lactam resistance of invasive H. influenzae isolates increased during the study period, due to an increase of β-lactamase negative β-lactam resistant NTHi. A clonal expansion of a β-lactamase negative ampicillin resistant (BLNAR) clone, frequently found in invasive disease, was suggested. <br/><br>
The ability of H. influenzae to bind laminin, and anchor the extracellular matrix through the adhesin Protein E was confirmed. Binding to complement regulators was not higher in invasive as compared to nasopharyngeal NTHi isolates, and thus did not seem central for invasive capacity. Speculation, but no comprehensive conclusion as to what host factors relate to invasive disease by H. influenzae in adults was possible.<br/><br>
The results suggest that the vaccination against H. influenzae type b remains very effective 20 years after it was introduced, but that continued surveillance of incidence and antimicrobial resistance of invasive Haemophilus disease is warranted. The results also suggest that ongoing research should focus on non-typeable H. influenzae, which today dominates all types of H. influenzae infections.},
  author       = {Resman, Fredrik},
  isbn         = {978-91-87189-33-3},
  issn         = {1652-8220},
  keyword      = {Haemophilus influenzae,sepsis,epidemiology,antimicrobial resistance,bacterial adhesion},
  language     = {eng},
  pages        = {150},
  publisher    = {Department of Laboratory Medicine, Lund University},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {Invasive disease by Haemophilus influenzae in Sweden in the era of the H. influenzae type b vaccine},
  volume       = {2012:70},
  year         = {2012},
}