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Invasive Haemophilus influenzae Infection and Breastfeeding: Aspects of epidemiology and immunology
Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
2001 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Invasive Haemophilus influenzae (Hi) infection is still an important cause of morbidity and mortality in the world. Vaccination against Haemophilus influenzae type b (Hib) has been implemented in many industrial countries during the 1990s with a dramatic decrease in mortality and morbidity due to Hib. This is in sharp contrast to the situation in developing countries where Hib is still a threat.

In a prospective study conducted in Örebro County, Sweden, between 1987 and 1992, before large scale Hib vaccination of children was introduced, the incidence of invasive Hi infection in children 0-4 years of age was 55/100 000 children/year. Hib caused 98% of the Hi cases in children.

In a case control study it was found that duration of exclusive breastfeeding less than 13 weeks as well as a history of frequent infections were independent factors associated with an increased risk of invasive Hi infection with odds ratios, OR, of 3.79 (1.6-8.8) and 4.49 (1.0-21.0) respectively. For the age at onset of 12 months or older, the associations were stronger, OR 7.79 (2.4-26.6) and 5.86 (1,1-30.6), respectively. When breastfeeding duration in weeks was analysed as a continuous variable the OR was 0.95 (0.92-0.99), indicating a decreased risk for each additional week of breastfeeding.

An ecologic study of the relation between incidence rates of Hi meningitis between 1956 and 1992 and breastfeeding rates in the population was performed. A strong negative correlation between breastfeeding and incidence of Hi meningitis was found with a maximum for a time Jag of 5-10 years. The correlation for contemporary data was intermediate. The result implies that a low breastfeeding rate was followed by an increased incidence rate of Hi meningitis up to 10 years later in time.

In two laboratory assays the anti-Hib antibody response was investigated in children with invasive Hib infection as well as in healthy children in relation to age, duration of exclusive breastfeeding, history of frequent infections and exposure to passive smoking. Children 18 months or older with a duration of exclusive breastfeeding of 13 weeks or more had higher levels of anti-Hib antibodies of the IgG1, IgG2 and IgM isotypes during the Hib infection compared to those less breastfed. The differences between the breastfeeding groups (<13 weeks versus ≥ 13 weeks) were greatest for the IgG2 isotype. In control children a duration of exclusive breastfeeding of ≥ 13 weeks emerged as a protective factor against non-invasive and non-specific infections with an OR of 0.92 (0.86-0.99). The protective effect was stronger in children < 18 months of age with an OR of 0.87 (0.76-1,0). Duration of exclusive breastfeeding was not associated with anti-Hib antibody levels in children < 18 months of age. In children ≥ 18 months of age there was a weak association between duration of exclusive breastfeeding and anti-Hib antibody levels of the IgG2 isotype, strongest in those without frequent infections. Expression of idiotype I (Id-1) antibodies increased with age in contrast to idiotype 2 (Id-2) antibodies that were found only in children ≤ 24 months of age, but the levels of neither Id-1 nor ld-2 were related to duration of breastfeeding or exposure to passive smoking.

In conclusion, exclusive breastfeeding seems to be protective against invasive Hi infections. Exclusive breastfeeding seems to be protective against Hi meningitis also at a population level. There are indications of a long lasting enhancing effect of breastfeeding on the antibody response to Hib in children, in particular on the IgG2 anti-Hib antibody production.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2001. , 59 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 676
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-28636Local ID: 13792ISBN: 91-7219-972-5 (print)OAI: oai:DiVA.org:liu-28636DiVA: diva2:249447
Public defence
2001-05-22, Willandersalen, M-huset, Regionsjukhuset, Örebro, 13:00 (Swedish)
Opponent
Available from: 2009-10-09 Created: 2009-10-09 Last updated: 2012-09-07Bibliographically approved
List of papers
1. Invasive Haemophilus influenzae Disease: Epidemiology and Clinical Spectrum Before Large-scale H. influenzae Type b Vaccination
Open this publication in new window or tab >>Invasive Haemophilus influenzae Disease: Epidemiology and Clinical Spectrum Before Large-scale H. influenzae Type b Vaccination
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1995 (English)In: Scandinavian Journal of Infectious Diseases, ISSN 0036-5548, E-ISSN 1651-1980, Vol. 27, no 1, 63-67 p.Article in journal (Refereed) Published
Abstract [en]

In a prospective study between January 1987 and December 1992, 103 patients with invasive Haemophilus influenzae (Hi) infection were identified in a well-defined population before large-scale Haemophilus influenzae type b (Hib) vaccination was introduced. The incidence (cases/100,000/year) of invasive Hi infection was 5.9 for the whole population, 55 for children 0-4 years old and as high as 2.8 for adults. Hib was the predominant cause of the infection (83 cases) in children but, in adults, 13/39 (30%) cases were caused by non-typable Hi and 6/39 (19%) by Hi serotype f. Three patients (3%) died and 6 (5.8%) suffered a permanent sequel from the infection. All patients with such a sequel had invasive Hib infection. No significant difference between patients 0-6 years old and matched controls regarding the frequency of subnormal serum levels of immunoglobulins was found.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-81106 (URN)10.3109/00365549509018974 (DOI)
Available from: 2012-09-07 Created: 2012-09-07 Last updated: 2017-12-07Bibliographically approved
2. Protective effect of breastfeeding on invasive Haemophilus influenzae infection: a case-control study in Swedish preschool children
Open this publication in new window or tab >>Protective effect of breastfeeding on invasive Haemophilus influenzae infection: a case-control study in Swedish preschool children
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1997 (English)In: International Journal of Epidemiology, ISSN 0300-5771, E-ISSN 1464-3685, Vol. 26, no 2, 443-450 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: In Orebro County a 2.5-fold increase in the incidence of Haemophilus influenzae (HI) meningitis was found between 1970 and 1980, an observation that initiated the present study.

MATERIALS AND METHODS: In order to search for associations between morbidity in invasive HI infection and possible risk factors, a case-control study was conducted over a 6-year period from 1987 to 1992, before general Hib vaccination was introduced in Sweden. Fifty-four cases with invasive HI infection 139 matched controls were studied for possible risk factors such as day-care outside the home, short duration of breastfeeding, passive smoking, low socioeconomic level of the household, many siblings in the family, allergy, frequent, infections, repeated antibiotic treatments and immunoglobulin deficiency.

RESULTS: Multivariate analysis showed a significant association between invasive HI infection and two independent factors, i.e. short duration (< 13 weeks) of exclusive breastfeeding, odds ratio (OR) 3.79 (95% confidence interval [CI] 1.6-8.8) and history of frequent infections, OR 4.49 (95% CI : 1.0-21.0). For the age at onset 12 months or older, the associations were stronger, OR 7.79 (95% CI : 2.4-26.6) and 5.86 (95% CI : 1.1-30.6), respectively. When breastfeeding duration in weeks was analysed as a continuous variable the OR was 0.95 (95% CI : 0.92-0.99), indicating a decreased risk with each additional week. Increased OR were observed for other risk factors as well but not of the magnitude found for short duration of breastfeeding.

DISCUSSION: The association of decreased risk for invasive HI infection and long duration of breastfeeding was persisting beyond the period of breastfeeding itself. This finding supports the hypothesis of a long-lasting protective effect of breastfeeding on the risk for invasive HI infection. CONCLUSION: A decreased risk for invasive HI infection with long duration of breastfeeding was found. Our results do have implications for strategies in breastfeeding promotion, especially in countries where Hib vaccination is too costly and not yet implemented.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-81107 (URN)10.1093/ije/26.2.443 (DOI)
Available from: 2012-09-07 Created: 2012-09-07 Last updated: 2017-12-07Bibliographically approved
3. Protective effect of breastfeeding: an ecologic study of Haemophilus influenzae meningitis and breastfeeding in a Swedish population
Open this publication in new window or tab >>Protective effect of breastfeeding: an ecologic study of Haemophilus influenzae meningitis and breastfeeding in a Swedish population
1999 (English)In: International Journal of Epidemiology, ISSN 0300-5771, E-ISSN 1464-3685, Vol. 28, no 1, 152-156 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: In Örebro County, Sweden, a 2.5-fold increase in the incidence of Haemophilus influenzae (HI) meningitis was found between 1970 and 1980. In a case-control study of possible risk factors for invasive HI infection conducted in the same area, 1987-1992, breastfeeding was found to be a strong protective factor.

MATERIAL AND METHODS: In order to study the relation between incidence rates of HI meningitis between 1956-1992 and breastfeeding rates in the population an ecologic study was performed.

RESULTS: A strong (negative) correlation between breastfeeding and incidence of HI infection 5 to 10 years later (rho(xy) (s) approximately -0.6) was seen, whereas no relation seems to exist for the time lag 15 years and beyond. The correlation for contemporary data was intermediate. There were similar results for the breastfeeding proportions at 2, 4 as well as 6 months of age.

DISCUSSION: Our ecologic data are consistent with results from our case-control study. The time-lag for the delayed effect on the population level could be estimated although sparse data make the estimates vulnerable to sampling fluctuations. Limitations with ecologic studies are discussed.

CONCLUSION: There seems to be an association between high breastfeeding rate in the population and a reduced incidence of HI meningitis 5 to 10 years later. These results do have implications on strategies for breastfeeding promotion, especially in countries where Hib vaccination is too costly and not yet implemented.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-26070 (URN)10.1093/ije/28.1.152 (DOI)10529 (Local ID)10529 (Archive number)10529 (OAI)
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
4. Long-term enhancement of the lgG2 antibody response to Haemophilus influenzae type b by breastfeeding
Open this publication in new window or tab >>Long-term enhancement of the lgG2 antibody response to Haemophilus influenzae type b by breastfeeding
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Subjects. Sets of sera were obtained from 30 children below 6 years of age with invasive Haemophilus influenzae type b (Hib) infection, and therr mothers. DuratiOn and mode of breastfeeding were registered. Levels of IgG1, IgG2, IgA and IgM antibodies agamst Hrb capsular polysaccharide (CP) were determined in sera taken during acute the illness as well as in the early and late convalescence.

Results. Children 18 months or older with longer duration of exclusive breastfeeding (13 weeks or more, mean 19.3 weeks) had higher anti-Rib antibody levels of the IgG1, IgG2, IgA and IgM isotypes than those with shorter duration of exclusive breastfeeding (less than 13 weeks, mean 5.4 weeks). The difference between the breastfeeding groups was greatest for the IgG2 isotype. In regression analyses the association between the duration of exclusive breastfeeding and the anti-Hib IgG2 level was significant when breastfeeding, type of Hib infection, maternal anti-Rib antibody level and age were used as explanatory factors. In the group of 14 children below 18 months of age no significant differences were noted.

Discussion. Human milk is rich in IFN-y as well as in IFN-y producing cells, which may result in a specific stimulatory effect of breastfeeding on the IgG2 anti-Rib antibody response. In conclusion, this study indicates the presence of a long lasting enhancing effect of breastfeeding on the antibody response to Hib in children, in particular on IgG2 anti-Hib antibody production.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-81108 (URN)
Available from: 2012-09-07 Created: 2012-09-07 Last updated: 2012-09-07Bibliographically approved
5. Breastfeeding in relation to non-invasive infections and anti-Hib antibodies in control children
Open this publication in new window or tab >>Breastfeeding in relation to non-invasive infections and anti-Hib antibodies in control children
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Subjects. Sera were obtained from 74 healthy children, below 6 years of age, recruited as controls in a case control study. Duration and mode of breastfeeding were registered. Frequent infections as stated by parents and levels of antibody to Haemophilus influenzae type b (Hib) were studied in relation to the duration of exclusive breastfeeding.

Results. Duration of exclusive breastfeeding emerged as a protective factor against frequent non-invasive and non-specific infections in all children with an OR of 0.92 (0.86-0.98), adjusted for passive smoking and sex. After stratification for age the OR decreased to 0.87 (0.76-1.0) in children less than 18 months indicating a stronger protective effect by exclusive breastfeeding against frequent non-invasive infections in younger children compared to older ones. In the younger children sex was the only significant factor associated with the anti-Hib IgG1 and IgG2 antibody levels. Duration of exclusive or any breastfeeding, used either as a dichotomised or a continuous variable, did not show any significant influence on the antibody levels in the younger children. In children ≥ 18 months of age the regression model for anti-Hib IgG2 antibody level was close to significance (p=0.052) but with only a very low R2 around 0.07. When frequent infections or passive smoking was added as an explanatory variable, duration of exclusive breastfeeding became significant (p=0.036) but still with a low R2 Duration of exclusive breastfeeding was significantly related to the anti-Hib IgG2 antibody level in older children without frequent infections. Expression ofldiotype-1 (Id-1) antibodies increased with age in contrast to Id-2 antibodies that were found only in children ≤ 24 months of age, but the levels of neither Id-1 nor Id-2 antibodies were related to duration of breastfeeding or passive smoking. In older children, those without frequent infections showed higher levels of antibodies expression Id-1 than children with frequent infections.

Discussion. Human milk contains oligosaccharides, leucocytes (granulocytes, macrophages and lymphocytes), hmmones, cytokines, growth factors and other substances that may protect against infection or stimulate the proliferation and the development of the innate and adapted immune system including a stimulatory effect on the anti-Hib antibody response. The distributions of Id-1 and Id-2 were related to age and the IgG2 anti-Hib antibody levels.

Conclusion. This study shows that exclusive breastfeeding is likely to have a protective effect against frequent non-invasive infections. It also shows that breastfeeding seems to enhance the anti-Hib IgG2 antibody production in healthy children.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-81109 (URN)
Available from: 2012-09-07 Created: 2012-09-07 Last updated: 2012-09-07Bibliographically approved

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