"Risk factors for invasive Haemophilus influenzae disease among children 2-16 years of age in the vaccine era, Switzerland, 1991-1993" (International Journal of Epidemiology, vol. 25, no. 6, December 1996, pp. 1280-5): "Continued surveillance, and detailed investigation of direct and indirect effects of conjugated vaccines and risk factors…are important." 143 cases with invasive disease were selected, and vaccination status ascertained. "Cases more often than controls reported suffering from asthma and allergies… The observed association between asthma and epiglottitis is novel and deserves further investigation."

Citations below taken from: Can Hib Vaccine Cause Asthma?----- Heidi White

Muhlemann K; Alexander ER; Weiss NS; Pepe M; Schopfer KRisk factors for invasive Haemophilus influenzae disease among children 2-16 years of age in the vaccine era, Switzerland 1991-1993. The Swiss H. Influenzae Study Group.   Int J Epidemiol 1996 Dec;25(6):1280-5 PMID: 9027536 UI: 97179250
ABSTRACT: BACKGROUND: Continued surveillance, and detailed investigation of direct and indirect effects of conjugated vaccines and risk factors for invasive H.influenzae serotype B (Hib) disease in the vaccine era are important. METHODS: 143 cases with invasive disease between 1991 and 1993 aged 2-16 years were selected retrospectively from a large incidence trend study. Controls (n = 336) were recruited from local vital registries and matched to cases for age, gender, and residence. Hib vaccination histories among study subjects and their siblings and other sociodemographic variables were obtained by questionnaires completed by the parents of these children. Adjusted odds ratio (OR) estimates were calculated by conditional logistic regression analysis. RESULTS: Most vaccinated subjects had received the Polysaccharide- Diphtheria Toxoid vaccine and estimated vaccine efficacy was high (95%; 95% confidence interval [CI] 60-99%). Also, the results suggested that protection afforded by vaccination against Hib extended to the family members of vaccinated children. School attendance was found to be protective against invasive Hib disease (OR:0.33; CI:1.2-14.4). Cases more often than controls reported suffering from asthma and allergies (OR:4.8; CI:1.2-19.4). CONCLUSIONS: Post-licensure vaccine efficacy is high among children > or = 2 years of age. The observed association between asthma and epiglottitis is novel and deserves further investigation.

Kurono Y; Yamamoto M; Fujihashi K; Kodama S; Suzuki M; Mogi G; McGhee JR; Kiyono H   Nasal immunization induces Haemophilus influenzae-specific Th1 and Th2 responses with mucosal IgA and systemic IgG antibodies for protective immunity. J Infect Dis 1999 Jul;180(1):122-32  PMID: 10353870 UI: 99282596
ABSTRACT: To determine the efficacy of a mucosal vaccine against nontypeable Haemophilus influenzae (NTHi), mice were immunized nasally, orally, intratracheally, or intraperitoneally with NTHi antigen together with cholera toxin. Antigen-specific IgA antibody titers in nasal washes and the numbers of antigen-specific IgA-producing cells in nasal passages showed the greatest increases in mice immunized nasally. Cytokine analysis showed that interferon-gamma, interleukin (IL)-2, IL-5, IL-6, and IL-10 were induced by nasal immunization, suggesting that Th2- and Th1-type cells were generated. Furthermore, bacterial clearance of a homologous strain of NTHi from the nasal tract was significantly enhanced in the nasal immunization group. These findings suggest that nasal immunization is an effective vaccination regimen for the induction of antigen-specific mucosal immune responses, which reduce the colonization of NTHi in the nasal tract.

Nijkamp FP, et al.  Facilitation of histamine release in the Haemophilus influenzae vaccinated experimental animal.    Br J Pharmacol. 1980 Jan;68(1):147P. No abstract available. PMID: 6153543 UI: 80131284

Raaijmakers JA; Terpstra GK; Kreukniet J  Mast cells as a possible source of Haemophilus influenzae-induced changes in plasma and lung histamine levels.   Int Arch Allergy Appl Immunol 1980;61(3):352-7  PMID: 6153378 UI: 80114589
ABSTRACT: Histidine decarboxylase activity and histamine levels of peritoneal mast cells were enhanced 4 days after intraperitoneal Haemophilus influenzae vaccination of rats. Incubation of the cells with propranolol (3.4 x 10(-4) M) resulted in histamine release and an increased histidine decarboxylase activity. Histidine decarboxylase activity and histamine release were more increased in the presence of propranolol in mast cells obtained from H. influenzae-vaccinated rats. An increased mediator release is also suggested by the increase of the number of peritoneal eosinophils. These data might explain the earlier observed enhanced plasma and lung histamine levels in H. influenzae- vaccinated rats.

Terpstra GK; Raaijmakers JA; Kreukniet J  Comparison of vaccination of mice and rats with Haemophilus influenzae and Bordetella pertussis as models of atopy.  Clin Exp Pharmacol Physiol 1979 Mar-Apr;6(2):139-49 PMID: 311260 UI: 79126330
ABSTRACT: 1. Rats and mice were vaccinated with Haemophilus influenzae in different vaccination schedules whereafter blood eosinophils were counted. In rats a single vaccination resulted in a dose-dependent effect on the blood eosinophil count in a pattern comparable with that after Bordetella pertussis vaccination. In a long-term vaccination schedule (five times a week for 5 weeks) rats developed a constant eosinophilia. In mice a single vaccination resulted in an eosinopenia of a consistent pattern which differed from the response after Bordetella pertussis vaccination; in a long-term vaccination schedule, eosinophilia was evoked for a period of about 13 days. 2. Thirty minutes after an adrenaline injection in vaccinated rats and mice with Haemophilus influenzae, hyperglycaemic and eosinophilic responses were measured. The eosinophilic response after adrenaline was inhibited in both species; the hyperglycaemic response in rats was unaltered, in mice the response was slightly but significantly (P less than 0.05) decreased. 3. The sensitivity to several drugs was tested in mice, 5 days after vaccination with Haemophilus influenzae or Bordetella pertussis. Haemophilus influenzae vaccination reduced the isoprenaline sensitivity and increased the noradrenaline sensitivity. Bordetella pertussis vaccination reduced the isoprenaline sensitivity while the sensitivity to histamine and adrenaline was raised. 4. The Haemophilus influenzae vaccinated experimental animal provides a model that is possibly more related to human atopy than the Bordetella pertussis vaccinated animal.

Terpstra GK; Raaijmakers JA; Hamelink M; Kreukniet JEffects of Haemophilus influenzae vaccination on the (para-)sympathic- cyclic nucleotide-histamine axis in rats. Ann Allergy 1979 Jan;42(1):36-40  PMID: 216288 UI: 79101862
ABSTRACT: To determine whether Haemophilus influenzae could be a factor in human atopy its effects were studied on the (para-)Sympathic Cyclic nucleotide-histamine axis in rats. Haemophilus influenzae vaccination induced changes in the cholinergic system compatible with higher cyclic GMP levels and enhanced histamine release. The authors suggest an involvement of the cholinergic system in Haemophilus influenzae vaccination effects.

Schreurs AJ; Nijkamp FP   Bronchial hyper-reactivity to histamine induced by Haemophilus influenzae vaccination.  Agents Actions 1984 Oct;15(3-4):211-5  PMID: 6335351 UI: 85118726
ABSTRACT: Bronchial hyper-reactivity to histamine 4 days following vaccination with the human respiratory pathogen Haemophilus influenzae was tested in two in vivo and one in vitro models. Conscious vaccinated guinea pigs exposed to aerosolized histamine became asphyxial significantly faster than saline-treated controls. Also the bronchoconstriction in anaesthetized guinea pigs as a result of i.v. histamine was significantly potentiated in the H. influenzae pretreated group. Isoprenaline (30 micrograms/kg) partially inhibited the bronchoconstriction. The difference in histamine sensitivity between the two groups however remained. Protection against bronchoconstriction by atropine on the other hand was significantly enhanced in the vaccinated animals. This suggests a hyper-reactivity of the parasympathetic, cholinergic pathways as a result of H. influenzae vaccination.

Terpstra GK; Kreukniet J; Raaijmakers JA  Changes in beta-adrenergic responses as a consequence of infection with micro-organisms.    Eur J Respir Dis Suppl 1984;135:34-46  PMID: 6329808 UI: 84236583
ABSTRACT: The B. pertussis model of atopy as proposed by Szentivanyi in 1968 has been a starting point for much research involving the pathogenesis of COLD. Moreover, it supplied more insight into the pharmaco-therapeutic approach toward this group of diseases. In this review, it is shown that products of bacteria considered to be a constituent of the normal flora of the human upper respiratory tract, such as H. influenzae, elicit changes in adrenoceptor responsiveness which are compatible with an enhanced tendency toward bronchoconstriction. One of the features of human atopy is enhanced mediator release after appropriate stimuli resulting in bronchoconstriction. This phenomenon can be mimicked in an animal model, the H. influenzae-vaccinated rat or guinea pig; enhanced histamine synthesis and release are found in vivo as well as in vitro. The effects point in the direction of a beta-adrenergic defect which is not only demonstrable in biochemical but also in physiologically oriented parameters. Pulmonary smooth muscle tissue appears to be less responsive to beta-adrenergic agonists and has an enhanced tendency to contract. The view that these changes are indeed the reflection of changes in adrenoceptor systems has been investigated in guinea pigs and rats. In both species impairment of beta-adrenergic systems together with a reduction in the number of beta 2-adrenoceptors was found after vaccination. Also the involvement of other factors, e.g., catecholamines, has been demonstrated. Comparable changes occur within the pulmonary adrenoceptor populations of COLD patients, suggesting disturbed homeostasis in the autonomic nervous system, possibly leading to bronchoconstriction. The question whether a bacterial factor is important in these changes and might induce, sustain or enhance the effects of other factors or even have a role in the pathogenesis of COLD is discussed in this review.

Schreurs AJ; Terpstra GK; Raaijmakers JA; Nijkamp FP   The effects of Haemophilus influenzae vaccination on anaphylactic mediator release and isoprenaline-induced inhibition of mediator release.  Eur J Pharmacol 1980 Apr 4;62(4):261-8  PMID: 6154589 UI: 80178911
ABSTRACT: The influence of Haemophilus influenzae on anaphylactic mediator release from ovalbumin-sensitized isolated guinea pig lungs was investigated. Lungs from H. influenzae-vaccinated animals released prostaglandins and thromboxanes following a smaller dose of ovalbumin than was effective in non-vaccinated animals. Histamine release was significantly increased in 4 day-vaccinated animals but not 1 or 10 days after vaccination, while bronchoconstriction was potentiated in 1 and in 4 day-vaccinated animals. This increased histamine release was achieved following 2 micrograms ovalbumin. In contrast, doses of 10 micrograms and 1 mg ovalbumin respectively did not affect and decreased histamine release in the vaccinated group. The inhibition of anaphylactic mediator release by an infusion of 6 x 10(-9) M isoprenaline was significantly attenuated by H. influenzae vaccination. These results indicate an increased sensitivity to antigenic challenge and suggest that the functioning of beta-adrenoceptors was decreased as a result of H. influenzae vaccination.

Schreurs AJ; Versteeg DH; Nijkamp FP Involvement of catecholamines in Haemophilus influenzae induced decrease of beta-adrenoceptor function.   Naunyn Schmiedebergs Arch Pharmacol 1982 Sep;320(3):235-9  PMID: 6290901 UI: 83037012
ABSTRACT: The deeper airways of patients with asthmatic bronchitis are often infected with Haemophilus influenzae. Vaccination of guinea pigs with H. influenzae resulted in a significant impairment of the isoproterenol induced relaxation of isolated tracheal spirals by approximately 50% 4 days following vaccination. In the present study we further investigated the effects of some drugs affecting catecholamine release on the H. influenzae induced functional desensitization of tracheal spirals. Benserazide, an inhibitor of dopa-decarboxylase, completely prevented the reduction in isoproterenol-induced relaxation after H. influenzae vaccination, while no effect on relaxation of tracheal spirals from control animals was detected. On the other hand, inhibiting the re-uptake of catecholamines with desipramine did not influence the relaxation in the H. influenzae vaccinated tracheal spirals. Treatment of control animals with desipramine however resulted in a decreased relaxation of the isolated spirals by 40%. One day following vaccination with H. influenzae the level of norepinephrine in lung tissue was significantly elevated by 71%, and in plasma by 77%, while after 4 days no significant effects were observed. The spontaneous release of norepinephrine, epinephrine and dopamine of tracheal incubates was increased at days 1 and 4 following vaccination. The release of catecholamines from minced lung incubates of H. influenzae pretreated guinea pigs did not differ from that of controls. On the basis of these results it may be suggested that catecholamine metabolism is changed in lungs from H. influenzae vaccinated animals. Catecholamines, accordingly may play a role in the desensitization of beta-adrenoceptors by H. influenzae.

Schreurs AJ; Terpstra GK; Raaijmakers JA; Nijkamp FP Effects of vaccination with Haemophilus influenzae on adrenoceptor function of tracheal and parenchymal strips. J Pharmacol Exp Ther 1980 Dec;215(3):691-6  PMID: 6969303 UI: 81071818
ABSTRACT: Haemophilus influenzae is a bacterium that can be isolated from the deeper airways of asthmatic patients. We investigated the effect of vaccination with H. influenzae on alpha and beta adrenoceptor function in guinea-pig tracheal spirals and lung parenchymal strips. The tracheal spirals from H. influenzae-vaccinated animals showed significantly less relaxation to isoproterenol as compared to controls, independent of whether the trachea was maximally contracted with carbachol or only exhibited an intrinsic tone. Furthermore, an increased contractile response to carbachol was observed in these spirals. To isoproterenol in the presence of a beta-2 adrenergic antagonist (H35/25), or to albutamol alone, the tracheal preparations from H. influenzae-vaccinated animals also showed a decreased relaxation. These results suggest involvement of both beta-1 and beta-2 subtype adrenoceptors. On the other hand, lung parenchymal strips from vaccinated guinea-pigs relaxed significntly more to these drugs. This effect was not influenced by H35/25 but could be inhibited by phenoxybenzamine. Histamine-induced contraction did not differ between the groups. These results indicated that H. influenzae causes a partial blockade of the beta adrenoceptors in tracheal spirals and, therefore, may have important implications in asthmatic bronchitis. In contrast, parenchymal lung strips of the H. influenzae-pretreated group showed an increased relaxation.

Nijkamp FP, et al.  Inhibition of effects of isoprenaline and adrenaline by Haemophilus influenzae vaccination.  Br J Pharmacol. 1980 Jan;68(1):146P. No abstract available. PMID: 6965598

Schreurs AJ; Verhoef J; Nijkamp FPBacterial cell wall components decrease the number of guinea-pig lung beta-adrenoceptors. Eur J Pharmacol 1983 Jan 28;87(1):127-32  PMID: 6301848 UI: 83182671
ABSTRACT: Infections of the deeper respiratory airways can contribute to the progression of chronic asthmatic bronchitis. In the present report a number of microorganisms affecting the number of beta-adrenoceptors in guinea-pig lung homogenates are described. Haemophilus influenzae, Streptococcus pneumoniae, Bordetella pertussis and Escherichia coli O111B4 induced a significant decrease of the number of beta- adrenoceptors (by approximately 20%). Staphylococcus aureus, influenza A virus and Escherichia coli J5 were not active. These data point to a common factor shared by gram-negative bacilli; i.e. endotoxin. Purified endotoxin of E. coli O111B4 also decreased the number of beta- adrenoceptors, while E. coli J5-LPS did not. This suggests that neutral polysaccharides of bacterial cell walls, especially those in the 'O'- antigenic side chain of gram-negative endotoxins may be responsible for the decrease of beta-adrenoceptor number and therefore contribute to the pathogenesis of chronic asthmatic bronchitis. Intact endotoxin seems to be necessary since neither the isolated lipid nor the polysaccharide part of E. coli O111B4 LPS affected the number of beta- adrenoceptors in the lung.