ET D'IMMUNOLOGIE CLINIQUE

REVUE FRANCAISE D'ALLERGOL~)GIE

Bronchial asthma and bacterial infection
A. OEHLING

KEY-WORDS: Asthma Pathophysiology.

Bacterial

infection

-

MOTS-CL1~S: Asthme Physiopathologie.

Infection bact~rienne -

In several publications, we have already emphasised the little importance given to the bacterial infection factor in the etiopathogenesis of bronchial asthma. This is, the role played by the bacterial antigens during the bacterial infection in the r h i n o s i n u b r o n c h i a l unit, assuming the responsibility of the inflammatory response, in both nasal and bronchial mucosa, and cause of the subsequent bronchospasm, the inflammation and obstruction. It is therefore surprising that in most publications regarding treatment of bronchial asthma, only the symptomatic t r e a t m e n t is considered and the bacterial infection factor is completely overlooked. It is alarming that even in the international consensus on treatment of bronchial asthma this aspect is totally ignored. In this kind of asthma, f r e q u e n t l y labelled as

dntrinsio,, we usually find that the treatment given is of the kind that ,,maintains,, asthma; this is, excessive treatments with bronchodilators and corticosteroids. The bacterial infection in the etiopathogenesis of bronchial asthma has been given great importance from the first decades of this century. Many of the pioneers in the study of this disease [1-6] emphasised that the recurring bronchitis with bacterial infection associated a bronchospastic component and they drew the attention to the close relation between infection and asthmatic reaction. Subsequently, from the 50s to the 70s, several authors among whom we are included [715] emphasise once again the importance of the bacterial infection factor in the etiopathogenesis of bronchial asthma.

Department of Mlergology and Clinical Immunology, University Clinic, Faculty of Medicine University of Navarra, PAMPLONA, (Spain). Correspondence : Pr. A. Oehling, Department of Mlergology and Clinical Immunology, University Clinic, Faculty of Medicine University of Navarra, PAIVlPLONA, (Spain). Interasma Marrakeeh' 98.

OEHLING A. - Bronchial asthma and bacterial infection. Rev. ft. Allergol., 1998, 38 (7S), $248-$257.

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/ BRONCHIAL ASTHMA AND BACTERIAL INFECTION •

$249 c h i l d h o o d asthma, has b e e n f r e q u e n t l y emphasised [16-19]. Our group, in a very large study p e r f o r m e d with a n u m b e r of cases and virus higher than any other study [32, 33], found a positive serology at the m o m e n t of the asthmatic crisis in only 14,5% of the children. Recently, other authors are insisting on the conjunction of the viral infection associated to the bacterial infection [25, 34]. The potentiating effect of the virus on bacteria-induced mediator release might be of importance for the conversion from latent to manifest asthma in upper respiratory tract infection. The e n h a n c e m e n t by influenza A virus of bacterial-induced histamine release may play a role in mixed bacterial and viral infections when the patient is sensitized to the bacterium in question. In our opinion, this is what usually happens when a viral infection starts and this is why we do not find it so important in bronchial asthma [32]. O f course, many rhinosinusal infections start with a viral infection (rhinovirus or others), but few days afterwards the association of a bacterial infection is very frequent, starting then an increase of hyperreactivity which affects the bronchial mucosa. This is what we have been observing for more than 40 years in the everyday clinical praxis. Taking into account that if we admit the action of the bacterial antigens with their corresponding humoral and cellular response we must consider that we will find IgE-mediated reactions, as well as reactions mediated by immunocomplexes and by cellular immunity. In this sense, several authors detect that specific IgE antibodies to bacteria can be identified in the sera of patients from a n u m b e r of respiratory diseases [35]. Pauwels in 1980 [36] demonstrated specific IgE against antigens to Haemophilus influenzae and Streptococcus pneumoniae; twenty-nine p e r c e n t of the investigated sera had such antibodies in bronchial asthma. The demonstration of IgE antibodies to bacteria in patients with bronchial asthma, both in the extrinsic and intrinsic asthma group, opens new perspectives for the study of the role of infection agents in asthma. Studies p e r f o r m e d on children with intrinsic bronchial asthma and with bacterial antigens demonstrate antigen-specific histamine release in the basophil, against a bacterial sonicate (fig. 2) [37]. Very important too are the studies p e r f o r m e d [27, 38] in relation with the results of challenge tests With bacterial antigens. The authors use the bronchial provocation as a 'model in bacterial b r o n c h i a l infections. T h e late r e a c t i o n is explained by a type Ill allergic reaction.

ASTHMA AND INFECTION BACTERIA mmuno ogica meclanism Bacterial antigens

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Fig. 1. - Immunological and non immunological mechanisms in infective asthma. T h e p r o b l e m of the bacterial allergy in bronchial asthma has probably been one of the most controversial aspects between Allergologists and Respiratory Disease Specialists in the last thirty years. Thanks to the advances of m o d e r n immunopathology, a more exact knowledge of the specificity of different bacterial antigens has been reached, in both in vitro diagnosis and challenge tests. In spite o f the detractors [16-19] of the i m p o r t a n c e of the i n f e c t i o n factor in the triggering of bronchospasm, it has been in recent years when norn [20-23] and many other authors [24-26] have demonstrated its responsibility at b r o n c h i a l m u c o s a level. This is how, the conclusion is drawn that the asthmatic response subsequent to a bacterial bronchiolar infection process can be triggered by an IgE-mediated response, by a response m e d i a t e d by o t h e r immunoglobulins, or subsequently by lectins from the own bacteria (fig. 1). In fact all these last publications confirm what many other authors had already demonstrated before, either from an experimental or from a clinical point of view [7, 8, 11, 27-31].

PRESENT SITUATION OF INFECTION IMMUNOPATHOLOGY: IMPORTANCE OF THE BACTERIAL ANTIGENS
The importance of the viral infection in the triggering o f intrinsic asthma, especially in
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Studies p e r f o r m e d by Holt et al. in recent years [39, 40] show the importance of the dendritic cells (DC), which are equivalent to the L a n g e r h a n s cells (LC) in the b r o n c h i a l epithelium, as presenting cells of the antigen. Studies p e r f o r m e d by these authors have shown that inhalation of bacterial LPS leads to rapid accumulation of DC in the airway epithelium and, by 24 hours after aerosol challenge, the density of the resulting intraepithelial DC net work can approach 200% of that seen in the steady state [41]. According to these authors bystander infections in the respiratory tract which occur concomitantly with exposure to inhalant allergen could stimulate the m i g r a t i o n of activated IFN(z/IL-12 secreting phagocytes from infected airway tissue into the regional lymph nodes. That is, bystander respiratory bacterial infections can directly modulate T H 1 / T H 2 selection in the i m m u n e response to inhalant allergens (fig. 3). Recently also holt [42] insists that one of the most potent exogenous stimuli identified for activation of antigen presentation mechanisms and IL-12 production by DC is interaction with microorganism, in particular LPS from bacterial cell walls. In figure 4, the dynamics of the bacterial infection, the role of macrophages and dendritic cells against bacterial antigens stimulating IL-12 production, can be seen; host responses to

<<bystander,, infections in respiratory tract produce further synergistic TH-1 selective cytokine signals. As we said b e f o r e a n d a c c o r d i n g to the mentioned authors [21-24, 26, 43] in their large and thorough studies the bacterial antigens are demonstrated to be able to release histamine in mast-cells and basophils (on one h a n d IgEmediated and on the other hand through the lectin) (fig. 5). Several strains of bacteria caused release of histamine f r o m h u m a n basophil leukocytes in vitro, and it is speculated that this release could be a pathogenic mechanism in intrinsic asthma. On the basis of these findings it is tempting to speculate that bacterial antigens reinforce the release of histamine caused by allergens in allergic patients or by bacteria in persons sensitized to bacteria, since it is well known that allergic symptoms are increased during infections [21, 23]. The IgE-mediated histamine release caused by specific antigens (allergens or bacteria) in sensitised individuals was e n h a n c e d by LPS. H i s t a m i n e release i n d u c e d by the specific allergens was enhanced by the bacterium. LPS from S. aureus and S. typhimurium i n d u c e d potentiation of histamine release by specific allergens in leukocyte suspensions from patients sensitized to house dust mite or birch pollen. That is, the histamine release induced by the
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specific allergens is enhanced by the bacterial LPS. An e n h a n c e m e n t of mediator release by bacteria or their components might play a role in the aggravation of bronchial asthma during infections [24] (fig. 6 and 7). Bacterial components
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such as peptidoglycan, teichoic acid and endotoxins from airway bacteria can aggravate allergic mediator release. In figure 8, the results obtained in a study p e r f o r m e d by us [44] can be seen, w h e r e d e m o n s t r a t e that the a n t i g e n

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Fig. 5. - Role of bacterial antigens and lectins in the asthmatic reaction.

Staphylococcus aureus potentiates at the maximum d e g r e e histamine release t o g e t h e r with the antigen D. pteronyssinus a n d especially in asthmatic patients with nasal secretion culture positive to the bacterium. In another study [45] and as can be seen in Table I, the differences between pollen allergic asthma and intrinsic asthma where the bacterial factor played an i m p o r t a n t role in the bronchoalveolar lavage, were proven. In this table we can see that there is an increase of CD4 in both kinds of asthma. By contrast, the pollinic form is characterized by an increase in IL-2R/CD25 and, in particular, an increase in IL-4 and CD23. In bacterial asthma an increase of IL-2, IFN-,/, and IL-5, among others, can be observed.

Finally and as far as the inflammatory response is concerned, to which more attention has been paid in r e c e n t years a l t h o u g h it has b e e n c o n s i d e r e d for many years essential in the asthmatic response, the substances responsible for it have also been study in depth. The cationic protein of the eosinophil (ECP) is probably the most studied among them, and whose importance we have already stated in a previous work [46]. Recently, Karawijczyk et al. [47] could follow the ECP levels in serum in the course of acute bacterial and viral infections. The mean values in controls (fig. 9) were 8,8 pg/1. Therefore, ECP levels and the subsequent inflammatory response are elevated when there is a bacterial infection. All this indicates that the eosinophil response is much higher in bacterial infection than in viral infection and the inflammatory compromise is also greater. Considering all the exposed, we would like to highlight that in r e c e n t years and t h r o u g h different articles emphasis is being put again on the little importance that bacterial antigens are given in the triggering of the asthmatic response. In this sense, the works by Norn et aL [48, 49, 50], Just [51], Jones [52], Hahn [53], H o f m a n n [54] and others stand out. All of them insist on the fact that the bacterial antigens assume the main responsibility in the i n f l a m m a t o r y and bronchospastic responses in the etiology of bronchial asthma during the respiratory infection.

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Table I. - I m m u n o l o g i c a l differences in BAL in two types o f bronchial asthma

SUBSEQUENT

TREATMENT

OF INFECTION
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> CD 4 < IL-2R / CD 25 > VLA-! / CD 29 > IL-2 > IFN-T > I1-5 > HLA-DR

T h r o u g h all the exposed and considering the importance of the bacterial infection factor in the etiopathogenesis of bronchial asthma, we must consider it very seriously when prescribing the treatment. Usually this aspect is overlooked and only treatment with bronchodilators is prescribed for bronchospasm and with ant|inflammatory

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Viral Bacterial Control possible, p e r f o r m a n c e of the c o r r e s p o n d i n g sputum or nasal secretion antibiogramme is suitable, which will show the germ or germs we are dealing with and the correct antibiotic. As this is often not possible, we advise the use of broad spectrum antibiotics, prescribing those against which we hardly ever find resistances. Obviously, if a causal treatment by means of bacterial i m m u n o t h e r a p y is going to follow afterwards, treatment of the infection would be logic and its repetition each time the focus appears. F r e q u e n t l y the relapses are the c o n s e q u e n c e of a viral infection b e c o m i n g bacterial subsequently (fig. 10).

Fig. 9. - S e r u m levels o f ECP in subjects with a c u t e viral o r b a c t e r i a l i n f e c t i o n s a n d in h e a l t h y controls.

corticosteroids for inflammation. It is just here where the most important mistakes are made. If we accept t h a t the bact_erial a n t i g e n i c components have a great responsibility in the triggering of bronchospasm, it would be obvious to eliminate as soon and as thoroughly as possible, the infection focus producing these antigens. This is, by means of treatment with broad spectrum antibiotics. Surprisingly, we find in the everyday praxis -that in patients who had been following a symptomatic treatment for many years treatment with a broad spectrum antibiotic is enough to eradicate bronchospasm and the subsequent bronchiolar hyperergic response. Since antibiotic therapy has been tried sometimes for these patients with common antibiotics such as Ampicillins and Amoxicillins, it is frequent to find that their bacterial flora is resistant to them. This is why it is advisable to use broad efficacyantibiotics in respiratory infections, such as gentamicin, erythromycin, josamycin, and recently ciprofloxacin, clarithromycin, roxithromycin and cefuroximes, the routine praxis makes these facts certain, of course, an optimal and lengthy therapy is very important in order to get the complete eradication of this bacterial infection factor. It is sometimes surprising the wrong dosages prescribed for antibiotic therapy and the short time for its administration, whose consequence is that the antibiotic action is not enough and the i n f e c t i o n focus is n o t e l i m i n a t e d c r e a t i n g resistances. In many cases, as long as this is

IMMUNOTHERAPY TREATMENT

Bacterial immunotherapy in the treatment of bronchial asthma of bacterial etiology was started many decades ago, and although it had some supporters such as Blatt [55] and others, it has also had some detractors. Nevertheless, and thanks to a better knowledge of the immunopathology of the bacterial factor in bronchial asthma, a bigger certainty about the immunological role of the bacterial antigens in the hyperergic reaction at bronchiolar level has been reached. This is, as we have already exposed before, the specificity of these antigens in the triggering of bronchospasm
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has been specified [27]. Of course, facing these facts, it is proper to think that the same as in the patient with bronchospasm due to sensitisation to some fraction of pollen antigen, immunotherapy with these antigens leads the target organ to a situation of hyporeactivity after contact with the mucosa, the same p h e n o m e n o n should take place when using bacterial antigens and identical immunotherapy techniques. In the last years the n u m b e r of authors who consider and argue very positively the role of the hyperergic response against the bacterial antigens has increased [15, 56, 57]. In several articles we have already stated our criteria regarding this problem and especially in recent years [58, 59] our experience has been enriched with very favourable results w h e r e we c o u l d observe extremely positive percentages for both adults and children. In a first group of adults with exclusively bacterial bronchial asthma, excellent results were obtain in 75%; this is, an important decrease of the bacterial infections and total elimination of the asthmatic symptomatology. Nevertheless, in children the percentage is even better increasing to 86,2%. We have already exposed in several occasions that the failure of bacterial i m m u n o t h e r a p y is basically due to a scarce bacterial concentration and extremely short periods of therapy, as it happens in the works performed by the detractors of this therapy [60-63].
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As far as therapy with bacterial antigens is concerned and in order to be successful it is absolutely necessary to follow a hyposensitisation scheme the same as with immunotherapy with airborne antigens. A period of at least three years is also important, and finally an efficient antibiotic in the infection relapses. These three points are basic and must be considered in the treatment of bronchial asthma of bacterial etiology. In patients with sensitisation to airborne antigens and for i m m u n o t h e r a p y with occupational or pollen antigens, we try to remove the patient fi-om h i s / h e r environment or we start a pre-seasonal treatment. This is why antibiotic treatment is so important for these patients. It would be very naive to think that only with bacterial i m m u n o t h e r a p y with no treatment against the bacterial focus we could obtain spectacular results [64].
CURING OR MAINTAINING ASTHMA

As a conclusion of all the exposed, the evolution of many asthmatic patients is very disappointing. T h e y are d o o m e d all their lives to follow treatments with bronchodilators and corticosteroids continuously, as a consequence of overlooking a causal treatment. Nowadays the excessive administration of corticosteroids, either oral or by inhaled route, is alarming, driving to a suprarenal insufficiency as we stated in a previous article based on our experience [65].

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° A. OEHLING /

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/ BRONCHIAL ASTHMA AND BACTERIAL INFECTION •
48. Clementsen E, Larsen EO., Milman N., Skov ES., Norn S. Haemophilus influenzae release histamine and enhance histamine release from human bronchoalveolar cells. APMIS, 1995, 103, 806812. 49. Kjaergard L.L., Larsen EO., Norn S., Clementsen E, Skov ES., Permin H. - Basophil-bound IgE and serum IgE directed against Haemophilus influenzae and Streptococcus pneumoniae in patients with chronic bronchitis during acute exacerbations. APM/S, 1996, 104, 61-67. 50. Norn S., Clementsen E, Larsen EO., Pertain H., Skov ES. Mechanisms in obstructive lung diseases: microorganisms induce and enhance mediator release. In: Progress in Allergy, and Clinical Immunology, Volume 4, Canc'n (M6xico) Eds. A.K. Oehling and J.G. Huerta L6pez, Hogrefe & Huber Publishers, 225-229.

$257 51. Just j., Fayon M., Charavel A., Grimfeld A. - Role of bacterial infections in children with asthma. Pediatr. PulmonoL, SuppL 1997, 16, 76. 52. Jones tL, Gruffydd-Jones K. - Management of acute asthma attacks associated with respiratory tract infection: a postal survey of general practitioners in the U.K. Respir. Med., 1996, 90, 419425. 53. Hahti D.L. - tiift:ctious asthma: a reemerging clinical entity?J. Faro. Pratt., 1995, 41, 153-157. 54. Hofinan J., Tobolczyk J., Pttchnarewicz A. - Specific IgE against bacterial antigens in children with bronchospastic symptoms. Int. Rev. AllergoL Clin. ImmunoL, 1997, 3, 149-152. 55. H. Blatt. - A Test to Ascertain the Patient's Specific Offending Allergens and Experiences in Desensitizing for these Allergens. Acta Allergol., 1959, XIII,, 279-285.

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Rev.fr Allergol., 1998, 38, 7S

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