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Journal of the Royal Society of Medicine Supplement No. 18 Volume 84 1991
Pathogenesis and management of lung disease in cystic fibrosis
Maximilian S Zach MD Department of Paediatrics, University of Graz, Universitats-Kinderklinik, Auenbruggerplatz, A-8036 Graz, Austria Keywords: cystic fibrosis; lung disease; bacterial infection; therapeutic concepts
Introduction Lung disease in cystic fibrosis (CF) is responsible for more than 95% of the morbidity and mortality characterizing this genetically determined disorder. Consequently, therapeutic advances in this field can be expected to have a major impact on quality of life and survival of patients. As a basis for categorizing and interrelating established as well as potential future therapeutic approaches, one has to review the complex relevant pathophysiology. The sum of presently established knowledge is sufficient for synchronizing recent advances in biochemistry, microbiology, immunology, pathology, and respiratory physiology into a coherent pathophysiological concept of disease mechanisms'. The basic and inherited functional defect in the respiratory mucosa is decreased apical membrane chloride channel conductance; this defect results in increased bacterial adherence and thereby facilitates initial bacterial colonization; to date, Pseudomonas aeruginosa (PA) is the predominating bacterial pathogen. Initial colonization is followed by a bacterial as well as by a host response; both have important implications for (a) persistence of bacterial infection, and, (b) tissue damage. Ongoing tissue damage results in progressive alterations of lung structure and function. Disease mechanisms The first step of this pathophysiological cascade, that is increased bacterial affinity and adherence to the respiratory mucosa of the CF patient, might be the most difficult one to investigate and understand, but, at the same time, might hold the greatest promise for effective future therapeutic intervention. Bacteria adhere by a specific interaction between their adhesins and receptors on cell surfaces and secretions; for nonmucoid strains of PA, these adhesins are pili, ie flexible filaments extending from the outer cell membrane; mucoid variants adhere by their gelatinous exopolysaccharide2-5. Intact mucosal defences, which are a combination of mechanical clearance, biochemical environment, and local immunity, will normally prevent bacterial binding. The CF-specific mystery, underlying the translation of an inherited epithelial ion transport defect into ineffective mucosal defences, has so far remained unresolved. It was frequently suggested that impaired mucociliary clearance, as caused by the epithelial chloride transport dysfunction, might be the crucial step that closes the gap between basic defect and bacterial colonization. It seems likely that CF epithelia provide insufflcient water to the surface liquids for avoiding inspissation of periciliary fluids and mucus6. Relevant studies, however, have remained inconclusive, as mucociliary transport rates have variously been found
as abnormal, normal, or even supranormal7'8. Thus, impaired mucociliary clearance in CF might as well be the consequence as the cause of bacterial infection. The same caveat might hold true for a variety of abnormalities in the cellular and humoral immunity that have been found in CF patients. Again, they might rather represent secondary diseas mechaniss; a clearcut primary defect in the systemic or mucosal immunity has so far not been documentedl6'910. A wide spectrum of abnormalities are either part of a reactive hyperimmune process, or due to toxic and proteolytic damage, as inflicted by hyperstimulated neutrophils or bacterial toxins'0"'1. Nevertheless, the search for more subtle primary defects is ongoing; presently, the finding of hypoglycosylated IgG, a quantitative elevation of nonopsonic IgG subclasses, inadequate immunological recognition of Staphylococcus aureus, and a reduced intraneutrophil killing rate in the presence of Cf-IgG-opsonins, are subject to discussion and research",6. Respiratory viral infections damage the mucosa and thereby facilitate bacterial adherence'2. In combination with an inherited defect of mucosal defences, they might become the crucial factor for tipping the balance in favour of bacterial invasion. Consequently, they become an important or even essential prerequisite for initial colonization'3. Staphylococcus aureus frequently binds to the mucosa as the first bacterial invader, inflicts damage on cell surfaces, and thereby sets the stage for subsequent pseudomonal infectionl"'4. Staphylococcus aureus might initially bind to cell surface fibronectin'5; the resulting loss of fibronectin facilitates adherence of PA16. This hypothesis could explain the characteristic sequence of bacterial invasion, but does not elucidate those initial mechanisms that support infection with Staphylococcus aureus. Whatever the mechanisms, whether uniform or variable, effective in combination, in sequence, or each by itself, the result is always initial bacterial colonization. The bacterial response to colonization is characterized by the expression ofthe mucoid phenotype of PA, which produces copious quantities of an extracellular polysaccharide, called alginate17. Those mechanisms in the host-bacterium interaction, responsible for this non-mucoid-to-mucoid transformation, have as yet not been fully elucidated, but the Fe2+/Fe3+ ratio present in the CF airway might be a crucial factor6. Alginate forms a wall around the bacteria, and, thereby protects the microorganisms against the patient's mechanical, cellular, and biochemical defenses. The volume of such an alginate-protected microcolony not only prevents macrophages and neutrophils from ingesting the bacteria, but also
Journal of the Royal Society of Medicine Supplement No. 18 Volume 84 1991
reduces the mechanical efficacy of mucociliary and cough clearance'8"19. It follows that expression of the mucoid phenotype of PA carries major responsibility for the chronic nature of the infection. In addition, bacteria produce a spectrum of extracellular virulence factors, which contribute to tissue damage and impair several aspects of 0ost immunity and mechanical defenses. PA elastase, a metalloenzyme, contributes as much as 20% of the total proteolytic activity in CF airway fluids, inactivates some ofthe patient's proteinase inhibitors, augments the proteolytic damage caused by neutrophil elastase, and disrupts immunoglobulins6.Other extracellular virulence factors inhibit the beating of respiratory cilia and damage ciliar ultrastructure20. By all these mechanisms, the bacterial response to the colonization of the CF lung further supports the persistence of the
invading microorganisms., The host response to colonization is even more complex. Accumulated evidence supports the hypothesis of a type HI hypersensitivity reaction, bridging the gap between PA infection and lung damage21-23. The bacterial invaders supply the antigens for an immune complex disease, that, via complement activation and generation of chemotactic split products, attracts large numbers of polymorphonuclear neutrophils to the airways; these hyperstimulated neutrophils release lysosomal enzymes and oxygen radicals during successful or frustrated phagocytosis, thereby subjecting the airway to high concentrations of hostderived, cytotoxic and proteolytic activity'. The important point in this immunological response is that the host tries to compensate for overwhelmed local defences by a hyperstimulated systemic immune. response. Thereby, the patient creates an immunological barrier between the heavily infected respiratory mucosa and the rest of his organism. To achieve this goal, however, neutrophils constantly release tissuedamaging and toxic substances in their battle against the microorganisms. Thereby effected local tissue damage is thus the price that is chronically paid for effective protection from systemic bacterial disease. The bronchial mucosa and wall structures acquire the role of a battle field, that is not only destroyed by the bacterial invaders, but also, and to an even greater extent, by the defensive actions ofthe host's systemic
immunity. Neutrophil-derived, proteolytic enzymes, namely elastase, cathepsin G, and peroxidase, can hydrolyse all major connective tissue proteins24-26. Normally, these proteases are immediately inactivated by a system of plasmatic and bronchial inhibitors. In CF sputum samples, however, more than 95% of elastase and 75% of cathepsin G are free and not bound to proteinase inhibitors; this ineffective defense against proteolytic attack is explained by proteolytic and oxidative inhibitor inactivation at the site of infection27. It follows that. the elastolytic activity in CF sputum is significantly higher than the one in the sputum of patients with chronic bronchitis or noninfected controls2829. The resulting degradation of connective tissue is responsible for a significantly elevated urine excretion of desmosines (elastin crosslinks); furthermore, there is abundant histological evidence for active elastolysis-in airway walls and bronchiectatic ulcers3. In addition, this host-derived proteolytic activity also facilitates the persistence of infection by cleaving immunoglobulins, damaging cell surfaces, and
impairing mucociliary clearance 31'32. Once this vicious circle is established, the chronic nature of the bacterial infection might progressively relate to the already present and constantly increasing amount of nonspecific damage, and, thereby, might ultimately become independent of the basic, inherited mucosal ion transport defect. It follows that any future and improved concept of therapeutic intervention should focus on earlier disease stages to effectively prevent, instead of ineffectively combat, the development of these self-perpetuating disease mechanisms. Ongoing proteolytic damage of bronchial tissue results in the destruction of airway wall structures. Consequently, bronchiectasis was and remains the predominant finding in studies of lung pathology-'336. Lungs in advanced disease stages reveal gross alterations in the volume proportions of anatomic lung components, namely a markedly increased volume proportion- of the airways, and, correspondingly, a decreased volume of parenchyma37 38. In addition, a spectrum of obstructive changes, like inflammatory mucosal oedema and airway plugging by mucopurulent secretions, contribute to a characteristic picture of structural alterations34-6. Lung pathology in CF is thus in good agreement with the above described immunological and biochemical concepts, and is readily expressed in the typical radiological pictures of the disorder3941. To date, it has remained unclear whether and to what extent these structural alterations are reversible by reparative mechanisms. Indirect evidence suggests, that growth of airway wall structures might be the only effective way to repair already inflicted damage'. Airways, however, grow mainly in infancy and early childhood, and this again draws our therapeutic attention to young age and early disease stages. Altered strture should reflect in corresponding alterations of lung function. Disease-inflicted functional damage is characterized by progressive obstruction of intrathoracic airways, due to inflammatory mucosal oedema, accumulated secretions, plus a variable component of bronchospasM4247. Obstructive changes lead to increased airflow resistance, hyperinflation, trapped gas, uneven distribution of ventilation, and, via ventilation-perfusion inequalities, to impaired gas exchange42 45. Disease progression can be closely monitored by lung function testing". It follows that all morphological findings that indicate airway obstruction are readily 2expressed by a: typical spectrum of lung function abnormalities. However, bronchiectatic airway dilation, the most prominent anatomic feature, does not correlate that readily with the physiological picture of the disease. Seemingly, the physiological expression of bronchiectasis is hidden behind a spectrum of obstructive changes. Theoretically, proteolytic airway wall damage should result in the mechanical consequence of airway wall instability4". On second glance, -when employing more sophisticated techniques of lung function testing, like superimposed partial and mnximum expiratory flow-volume curves, or isovolume pressure-flow curves, one can in fact demonstrate markedly increased distensibility and compressibility of central intrathoracic airways4O'. From a physiological viewpoitt, lung disease in CF can thus be understood as a variable combination of peripheral, in part bronchospastic, airway obstruction, and central, mainly bronchiectatic, airway instability49. This 'airway instability concept- offers an
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explanation for the typical shape of the maximum expiratory flow-volume curve in CF, correlates to earlier observations of an increased anatomical dead space, and has some relevance for the interpretation of common pulmonary function tests to the clinical monitoring of CF patients'. Most important, however, this concept widens the scope of our understanding of CF-specific lung function changes into a direction that allows for a complete agreement between the biochemical and anatomical features of the disease on one side, and its presentation in the lung function lab on the other. Furthermore, airway wall instability is a determining factor for the validity of bronchodilator medication, and for the mechanical efficacy of coughing and forced expiratory chest physiotherapy manoeuvres in the clearance of intrabronchial secretions.
Therapeutic concepts The described sequence of disease mechanisms offers a system for categorizing established as well as potential future therapeutic approaches. This review will not speculate on the possibilities of gene therapy. Presently, a wide spectrum of research activities is focused on the 'CF transmembrane conductance regulator', ie that genetically defective protein, responsible for the reduced apical membrane chloride channel activation. As yet, however, there is no effective pharmacological way to stimulate these defective chloride channels in the airway epithelium. In addition to reduced chloride channel activity, however, the sodium absorption in the respiratory mucosa is abnormally elevated52. Based on the assumption that inspissation of secretions by augmented water absorption and/or reduced water secretion plays a role in the pathogenesis of CF lung disease, a therapeutic reduction of excess sodium absorption comes into focus. Selective sodium transport blockers can inhibit this increased sodium absorption. One representative of this group is amiloride, a diuretic agent, that when applied to the luminal side of the respiratory epithelium can normalize the CF-specific, increased transepithelial potential difference52'53. First clinical trials in patients with CF have shown that the repeated inhalation of amiloride is without side-effects, increases the sodium content of sputum, and markedly enhances mucociliary clearanceM,55
Notwithstanding these first encouraging results, this approach is still far from becoming a routine in the treatment of CF lung disease. Amiloride has only a very short duration of action and longer acting similar substances must be developed. Therapeutic trials in patients with fully developed lung disease do not ideally comply with the above pathophysiological concepts. Ultimately, these substances will have to be investigated as to their potency in reducing the increased bacterial affinity to the respiratory mucosa; thus, future trials should focus on the prevention of bacterial colonization in very young patients. As an alternative or adjunct to a therapeutic correction of the basic ion transport defect, initial bacterial colonization could be prevented by inhibition of bacterial entry into the lower respiratory tract. This could be achieved by effective anti-PA immunotherapy. Passive immunotherapy with intravenously administered gamma globulin, enriched for PA lipopolysaccharide antibodies, was shown to decrease sputum PA density, increase serum anti-PA opsonic
activity, and improve clinical scores as well as lung function status56. However, such passive infusion of opsonic antibodies will always remain an intervention with short-term character, and long-term induction of opsonic anti-PA immunity by early vaccination seems to be a more compelling goal57. Early clinical trials, however, have led to disappointing results58. Current work aims at the development of vaccines which are directed against three important surface components of PA: pili, lipopolysaccharide, and alginate59. Clearly, the object is to reduce bacterial affinity to mucosa and secretions. One of the factors hampering such developments is the large variation in the carbohydrate ligands of tracheobronchial mucins which are recognized by different bacterial strains60. Nevertheless, candidate vaccines are in various stages of clinical evaluation57. The most simple approach to the prevention of initial bacterial colonization would be selective oral decontamination. First trials, however, remained unsuccessful in eliminating oropharyngeal PA61. Effective antimicrobial chemoprophylaxis, which, in contrast to conventional antimicrobial chemotherapy, is not concerned with established bacterial infection, but -is rather instituted right after CF has been diagnosed and is subsequently maintained on a long-term basis, might also be achieved by a regimen of inhaled antibiotics. As yet, this strategy is not sufficiently evaluated for clearly defining its preventive potential and limitations. Long-term inhalation of aminoglycosides was shown to be without side effects in patients with CF62. The CFcentre in Graz is presently reviewing more than 5 years of experience with a long-term strategy of inhaled antibiotics in young patients, instituted immediately after the first evidence for bacterial colonization has been noted. Compared with historical controls, this strategy appears as both safe and highly effective in preventing PA colonization and disease progression. Recently published observations from another centre seem to confirm this clinical impression and demonstrate that chronic lower airway colonization can be prevented or delayed by such an approach63. Such early institution of longterm treatment would be aided by new techniques for detecting the first signs of bacterial colonization as early as possible6. Nevertheless, all this is still chemotherapy and not chemoprophylaxis, albeit initiated at a very early disease stage. Based on such encouraging first experiences with early anti-PA chemotherapy, however, one can speculate that true prophylaxis, that is medication before initial bacterial colonization is established, might be a realistic therapeutic option and thus should become subject to large-scale clinical investigations. Probably the most effective way to protect the lower respiratory tract of young CF patients against bacterial invasion would be a combination of long-term inhaled anti-PA therapy with continuous or intermittent antistaphylococcal medication. One or a combination of several of the above strategies could develop into an effective approach for preventing bacterial adherence and initial colonization; as these concepts are concerned with the starting point of the entire disease process and do not have to deal with any secondary damage, they might hold the greatest promise for an early and effective conservation of lung structure and function.
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With established bacterial colonization, the bacterial response to the new environment, especially the production of alginate by mucoid strains of PA, offers itself as another promising target for the development of novel therapeutic tools. Once the enzymes involved in the biosynthesis are completely identified, specific inhibitors of alginate biosynthesis could be designed; alternatively, alginate could be attacked by enzymatic cleavage of the polysaccharide chain, using an alginate lyase 7. Such approaches might increase the effectiveness of antibiotic intervention; as yet, however, these anti-alginate strategies have not developed into the stage of clinical application. So far, this review has discussed novel or even experimental approaches; when now turning towards the therapeutic interaction with the host response, we have to focus our attention first on so-called 'established' strategies. Antimicrobial chemotherapy is considered the mainstay of today's therapeutic concepts; it interacts with the above discussed disease mechanisms by reducing the antigenic supply for the immunological cascade towards lung damage, by reducing the production of bacterial virulence factors, and by thereby interrupting the vicious circle of mucosal damage and bacterial adherence. Antimicrobial chemotherapy of CF lung disease has been and still is subject of a large and constantly increasing number of publications65; nevertheless, there are countless details that are still open to debate. While there is no question that antistaphylococcal intervention is highly beneficial or even life-saving in selected cases, the value of anti-PA chemotherapy has remained less obvious and is subject to ongoing controversy. On one side, there is the observation of a dramatic decrease in the annual mortality rate of the Danish CF centre after institution of intensive and regular antipseudomonal chemotherapy", and other such evidence for the long-term benefit from antibiotic treatment has accumulated in other centres. Seemingly in contrast to these findings are the results of a Canadian study, that compared active anti-PA chemotherapy with placebo in patients hospitalized with respiratory exacerbations, and remained unable to document a better short-term outcome for the actively treated group than for those receiving placebo67. Other authors again found that hospitalized CF patients showed more lung function improvement with intravenous antibiotics plus bronchodilators and chest physiotherapy, than with bronchodilators and physiotherapy alone; furthermore, they could correlate the induced decrease in sputum PA density with the obtained improvement in lung function" 69. Indirectly, the finding of an antibiotic-induced decrease of neutrophils and neutrophil mediators supports these clinical observations70. Some of the ongoing controversy around the question of anti-PA therapy might be explained by the frequently employed but nevertheless potentially misleading concept of short-term studies. The whole pathophysiological cascade from initial colonization to tissue damage drives an ongoing but gradual disease progression; consequently, anti-PA intervention should mainly effect the long-term course of the disease. One could speculate that some of the frequently observed dramatic improvements with antimicrobial chemotherapy might rather be due to the antistaphylococcal effect of such treatment courses, while their anti-PA effect might better be assessed by
focusing on the long-term course of the disease. This, however, suggests that numerous studies, which had concerned themselves with the short-term effects of antimicrobial intervention, might have produced results of limited relevance. In summary, there is little doubt that CF patients owe some of their increased life-span to today's consequent and individualized use of antimicrobial chemotherapy. This ongoing battle for individual survival, however, leads to a considerable selective pressure towards colonization by other and more resistant strains. This means that the survival of the individual patient is paid for by the development of a more difficult therapeutic situation; or, in other words, therapeutic efficacy today might well be based on loans that have to be repaid in the future. Chest physiotherapy is another traditional approach to the treatment of CF lung disease. So far, the rationale behind its daily application was to reduce the mechanical consequences of obstructing secretions like atelectasis, increased airflow resistance, and hyperinflation71. Since effective chest physiotherapy, however, clears mucopurulent secretions, it should also reduce the antigenic supply and the proteolytic activity in the patient's airways and should thereby help to prevent tissue damage" 71. If chest physiotherapy not only opens airways but also prevents tissue damage, it should have a beneficial long-term effect on the course ofthe disease. Long-term studies, however, are scarce, but have so far produced encouraging results72'73. Beneficial short-term effects of chest physiotherapy have been documented for various therapeutic methods71; recent results suggest that the improvement in lung function, frequently observed in hospitalized CF patients, can be dissected into a series ofphysiotherapy-effected steps and thus might depend on chest physiotherapy to a larger extent than previously acknowledged74. In addition to conventional chest physiotherapy (gravity-assisted drainage, chest clapping and vibration, assisted coughing), a spectrum of altemative methods, like the Forced Expiration Technique, Autogenic Drainage, Low-Pressure and High-Pressure PEP-Mask-Therapy, have been developed71. The relative value of these different techniques has so far not been established, and comparative studies are urgently needed. Clearly, the concept for the future is an individualized prescription of different techniques, carefully tailored to the needs of any specific patient, and guided by a detailed evaluation of the patient's disease stage, sputum characteristics, and lung function status. The concept of a hyperactive systemic immune response, ineffective in clearing microorganisms, but responsible for progressive tissue damage, suggests a role for anti-inflammatory agents. First studies of a long-term steroid medication could demonstrate some beneficial effects on the respiratory status of the patients75. A later re-evaluation of the same patient group, however, found a substantial impairment of growth, and, in some patients, glucose intolerance, early cataract, multiple bone fractures, and cushingoid appearance76. One wonders whether steroids, in dosages low enough to avoid such side-effects, and to be accepted by patients, can really suppress the systemic immune response sufficiently for altering the disease course. This caveat, however, does not apply to other disease situations, like symptomatic airway hyperreactivity, especially when associated with
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allergic bronchopulmonary aspergillosis, where steroid treatment is frequently needed for support of bronchodilator medication77. Clearly, the question of a routine steroid medication for CF patients requires further evaluation; important data can soon be expected from relevant large multicentre trials. Nonsteroidal anti-inflammatory agents are also under investigation7879. More aggressive immunosuppressive therapy, employing cytotoxic substances, holds some promise for slowing the progression of tissue damage as well; recently published preliminary results could document a beneficial effect of low-dose methotrexate therapy on the clinical and lung function status of CF patients in advanced disease stages80. Theoretically, however, such a strategy could also result in a breakdown of the inflammatory barrier that separates the infected mucosa from the rest of the organism; thus, this therapeutic concept might not be without the risk of extrapulmonary bacterial disease. The next potentially accessible step in the described cascade of disease mechanisms is proteolytic airway wall damage. The elastase-antielastase imbalance, invariably present in the airways of patients with advanced disease, could be counterbalanced by a treatment with inhibitors of neutrophil-derived elastase. Such elastase inhibitors were initially developed to treat emphysema, can be produced by recombinant DNA technology or by purifying human al-antitrypsin, and have demonstrated substantial inhibitory activity on CF sputum elastase in vitro8'. First clinical trials of topically applied inhibitors have been hampered by side-effects, but, since then, new substances have been developed. A recently reported clinical trial of intravenously applied human plasma al-antitrypsin succeeded in re-establishing the epithelial anti-neutrophil elastase screen and was tolerated without side-effects82. Subsequent recent experience showed a higher efficacy of topical application, ie twice daily inhaled aerosol therapy. One of the remaining problems is the inactivation of the therapeutic inhibitor by the locally increased oxidant burden; consequently, experiments to produce recombinant, oxidant-resistent al-antitrypsin are on their way. These are highly promising developments that have to be evaluated on a broader clinical scale. Finally, the possibilities to interact with altered structure and function have to be reviewed. Provided that growth of airway wall structures is truly the major reparative mechanism for bronchiectatic destruction, nutritional rehabilitation might have a significant impact on the respiratory disease course. Airways, however, will only be able to grow in a growing child. As airways gain in size mainly in infancy and early childhood, nutritional support should be most beneficial when provided early in life'. Later, in phases of no or only insignificant growth of bronchi, its respiratory effects might be minimal. This theory finds some support from studies of nutritional rehabilitation in older CF patients, which documented a catch-up growth of body mass without a clearcut improvement of lung function83 i. In contrast, another investigation of younger patients could demonstrate a sustained improvement of respiratory functions in response to nutritional therapy85. Furthermore, one tends to find the best survival statistics in centres that have a tradition of early and aggressive nutritional management. One can thus summarize that nutritional rehabilitation
interacts reparatively with airway wall damage, provided it is supplied early enough for effectively supporting growth of airway wall structures. When considering therapeutic interaction with altered respiratory function, modification of bronchial smooth muscle tone comes into focus. As discussed in the previous chapter, CF lung disease is characterized by a rather complex and variable combination of more central, bronchiectatic, airway wall instability, and more peripheral, in part bronchospastic, airway obstruction. Airway wall stability is determined by structural factors but also by bronchial smooth muscle tone86. Bronchodilators relax bronchial smooth muscle and thereby interact with this system in a complex way. On one hand, they reduce bronchospastic airway obstruction; on the other, they can also further destabilize damaged bronchi49. This again can reduce the mechanical efficacy of coughing and forced expirations for clearing secretions. In fact, increased airway compressibility is the classical mechanical handicap for many chest physiotherapy techniques in these patients. Whether the beneficial or the negative effect predominates in the individual patient, is determined by the momentary combination of mechanical factors; in the majority of cases, bronchodilators are beneficial but there are patients and treatment situations where they are clearly a handicap49-51. This outlines the necessity of an individualized approach, in this case guided by repeated and more sophisticated lung function testing. There is finally a rather complex and expensive surgical approach to interact with altered structure and function. Double-lung or heart-lung transplantation has rendered end-stage lung disease accessible for therapeutic intervention, and thus has brought hope to the hopeless87. The long-term prognosis of this complex and expensive procedure, however, is as yet somewhat uncertain; consequently, heart-lung-transplantation is still to be considered as experimental therapy. Even if this long-term prognosis proves to be good, and sufficiently specialized centres develop on a global scale, limited donor organ availability will most likely prevent this procedure from becoming the general solution for advanced CF lung disease88. In summary, this is the spectrum of established as well as expected therapeutic approaches, ordered in a sequence that complies with the initially outlined, newly developed, and coherent pathophysiological concept of disease mechanisms. All the currently developed, new strategies will still have to pass the stage of extensive clinical investigation. If shown to be both safe and effective, some of these new approaches might significantly modify presently established therapeutic habits. In order to separate essential from less important components, some of the more traditional, but in some aspects still empirical, therapeutic strategies should also undergo further clinical investigation.
Therapeutic problems Last but not least, there are several significant weaknesses and shortcomings of the presently employed treatment strategies. The medical approach to the treatment of CF lung disease tends to be uniform and thereby pays little tribute to the wide interindividual and longitudinal variations in the prevailing pathophysiology. This unsatisfactory situation is perpetuated by a
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traditionally poor definition of the relative value of different diagnostic parameters for tailoring more individualized treatment programmes. Secondly, the routine handling of the available therapeutic tools is usually simplified by overlooking countless pathophysiological interactions between different lines of treatment, like, for example, chest physiotherapy and bronchodilators, or antimicrobial chemotherapy and immunosuppressive intervention. For maximum efficacy, the entity of an individual treatment programme should ideally consist of optimally interacting parts. Last but not least, the present therapeutic routine does mainly address full-blown lung disease, and, in most cases, remains unsuccessful in interrupting an already established vicious circle of mucosal damage and bacterial infection. As outlined previously, the disease at this stage is not only perpetuated by the basic defect, but also by secondary damage. New and better therapeutic strategies should focus on earlier disease stages; improved diagnosis should aim at anticipating rather than registering lung damage. The aim of such concepts would be to get ahead ofthe disease process, instead of stumbling constantly behind. As outlined before, maximally effective intervention should ideally address the earliest disease stage, that is the basic defect or its translation into bacterial adherence. Patients and parents occasionally introduce another spectrum of faults into the treatment of CF lung disease, and poor compliance with medical recommendations has become a frequently experienced phenomenon. 'Self-treatment', probably motivated by a misinterpretation of the necessity to be an informed patient, often results in incomplete, ineffective, or even risky therapeutic approaches. 'Doctor-and-treatmentshopping', based on the somewhat naive concept of 'getting the best from everywhere', neglects the fact that different parts of a therapeutic programme have to be matched carefully for optimal interaction. So-called 'alternative treatment concepts' are typically characterized by a combination of two features, which are enthusiastic propagation on one side and a total lack of scientific evidence for effectiveness on the other; nevertheless they seem to radiate a weird kind of attraction for many patients and parents. While all these problems might appear as trivial to the academically-oriented researcher, they seriously threaten to hamper the translation of medical and scientific progress into therapeutic reality.
Conclusion Lung disease in CF is not a static entity. The relevant pathophysiology is subject to ongoing changes, which are mainly perpetuated by treatment and ongoing alterations in type and resistance of bacterial colonizers. Consequently, lung disease in CF 20 years ago might have differed in many details from the disease today, which again might differ from the disorder, that could have developed one or two decades from now. Thus, the presently experienced therapeutic struggle is not a static problem but has rather acquired the character of a running battle. The clinician, previously impressed by the impact of treatment on the survival of patients, is today facing up to a distinctively different disease, characterized by multiresistant
bacterial invaders and previously unexperienced late disease stages. Thus, the CF-caregiver is challenged to get ahead of an ongoing escalation in the complexity and severity of the disorder. The new therapeutic approaches discussed above offer themselves as urgently needed further advances against this continued and relentless challenge, and, if employed in a constructive co-operation of caregivers, parents, and patients, hold considerable promise and hope for the future. References 1 Zach MS. Lung disease in cystic fibrosis - an updated concept. Pediatr Pulmonol 1990;8:188-202 2 Woods DE, Strauss DC, Johanson WG, Berry VK, Bass JA. Role of pili in adherence of pseudomonas aeruginosa to mammalian buccal epithelial cells. Infect Immun 1980;29:1146-51 3 Ramphal R, Pyle M. Adherence of mucoid and nonmucoid pseudomonas aeruginosa to acid-injured tracheal epithelium. Infect Immun 1983;41:345-51 4 Ramphal R, Sadoff JC, Pyle M, Silipigni JD. Role of pili in the adherence of pseudomonas aeruginosa to injured tracheal epithelium. Infect Immun 1984;44:38-40 5 Ramphal R, Pier GB. Role of pseudomonas aeruginosa mucoid exopolysaccharide in adherence to tracheal cells. Infect Immun 1985;47:1-4 6 Fick RB. Pathogenesis of the pseudomonas lung lesion
in cystic fibrosis. Chest 1989;96:158-64 7 Sanchis J, Dolovich M, Eng P, et aL Pulmonary mucociliary clearance in cystic fibrosis. N Engl J Med
1973;288:651-4 8 Yeates DB, Sturgess JM, Kahn SR, Levison H, Aspin N. Mucociliary transport in trachea of patients with cystic
fibrosis. Arch Dis Child 1976;51:28-33 9 Schiotz PO. Systemic and mucosal immunity and nonspecific defence mechanisms in cystic fibrosis patients. Acta Paediatr Scand 1982;suppl. 301:55-62 10 Talamo RC, Schwartz RH. Immunologic and allergic manifestations. In: Taussig LM, ed. Cystic fibrosis. New York: Thieme-Stratton, 1984:175-93 11 Hornick DB. Pulmonary host defense: defects that lead to chronic inflammation of the airway. Clin Chest Med 1988;9:669-78 12 Ramphal R, Small PM, Shamas JW, et aL Adherence of pseudomonas aeruginosa to tracheal cells injured by influenza infection or by endotracheal intubation. Infect Immun 1980;27:614-19 13 Marks MI. Respiratory viruses in cystic fibrosis. N Engl J Med 1984;311:1995-6 14 Mearns MB, Hunt GH, Rushworth R. Bacterial flora of respiratory tract in patients with cystic fibrosis, 1950-1971. Arch Dis Child 1972;47:902-7 15 Kuusela P. Fibronectin binds to staphylococcus aureus. Nature 1978;276:718-20 16 Woods DE, Bass JA, Johanson WG, et aL Role of adherence in the pathogenesis of pseudomonas aeruginosa lung infection in cystic fibrosis patients. Infect Immun 1980;30:694-9 17 Russell NJ, Gacesa P. Chemistry and biology of the alginate of mucoid strains of pseudomonas aeruginosa in cystic fibrosis. Mol Aspects Med 1988;10:1-19 18 Lam J, Chan R, Lam K, Costerton JRW. Production of mucoid microcolonies by pseudomonas aeruginosa within infected lungs in cystic fibrosis. Infect Immun 1980;28:546-56 19 Baltimore RS, Mitchell M. Immunologic investigations of mucoid strains of pseudomonas aeruginosa: comparison of susceptibility to opsonic antibody in mucoid and nonmucoid strains. J Infect Dis 1980;141:238-47 20 Hingley ST, Hastie AT, Kueppers F, Higgins ML, Weinbaum G, Shryock T. Effect of ciliostatic factors from pseudomonas aeruginosa on rabbit respiratory cilia. Infect Immun 1986;51:254-62
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