Education and debate

Recent Advances: Respiratory medicine

^a Royal Brompton Hospital, London SW3 6NP

Clinical and molecular technological advances have transformed our understanding and knowledge of the complexities of respiratory disease over the past 20 years. Set against this background of rapid advances, this review will highlight some of the key recent developments during the past 12 months that are likely to influence clinical practice.

Asthma

Asthma is an important medical and social issue in the community, which will probably continue to have an impact on hospital resources throughout the 1990s. The number of admissions in England and Wales rose exponentially from just under 20000 a year in the 1960s to about 100000 in the 1980s.¹ Although the rate now seems to have stabilised, no evidence exists for a decreasing trend in hospitalisation or mortality.

Death rates continue to cause concern. Lang and Polansky reported patterns of mortality in Philadelphia and found an increase in the rate of death from asthma, from 1.68/100000 population in 1969 to 2.41/100000 in 1991.² Contrary to common belief, this increase was not related to air pollution, measures of which showed a substantial improvement over the same period. The most important risk factors for death from asthma were being poor and being black. A second study, in contrast, found no increase in the expected number of deaths associated with asthma in residents of Rochester, Minnesota, a community in which 96% are predominantly middle class and white.³ The geographical variation in the prevalence of asthma has been too pronounced and the population increase too rapid for these to be attributable to genetic factors, suggesting that important environmental influences may be operating. Although multiple factors such as quality of health care, health education, and living conditions are likely to be important, the studies raise important questions about predisposition and causation.

RELEVANCE OF ENVIRONMENTAL FACTORS

If pollution is not the cause of the increased prevalence of asthma then what is? Do environmental factors have any relevance? Studies of asthma caused by agents inhaled at work support the influence of environmental factors.⁴ An investigation of staff working with laboratory animals found a direct relation between the measured concentration of allergens in the air and the incidence of new respiratory symptoms and positive results to skin prick tests for rats' urinary protein.⁵ In particular, there seems to be a "window of susceptibility" of 1-2 years, during which the manifestation of hypersensitivity develops and the modifying effects of smoking (enhancing the likelihood of developing an allergy) are at their peak. These observations are consistent with the knowledge that infant sensitisation may also occur within a critical period after first exposure to ambient allergens. A good example of the value of identifying cause is the prevention of asthma induced by soy beans in Barcelona. The unloading of soy beans in the port caused outbreaks of asthma; identification of the cause resulted in filters being installed in the silos, and this eliminated outbreaks that had previously caused major morbidity including admissions to an intensive care unit.⁶

In the context of an increase in asthma and in deaths from asthma it is crucial that we learn more about causation. Increasing our understanding of the nature of the inherited predispositions and their interaction with environmental influences are central to any strategy designed to reduce the incidence of asthma.

Molecular genetics

Molecular science has provided clinical scientists with powerful tools to dissect and understand mechanisms of disease, particularly the chronic inflammatory diseases. Techniques such as microsatellite mapping and restriction fragment length polymorphism analysis can be used to identify individuals at risk of disease. With single gene defects such as (alpha)1 antitrypsin deficiency and cystic fibrosis this task is now fairly easy, and the means are being developed to correct deficiency by administering the protein (in the case of (alpha)1 antitrypsin) or replacing the defective gene with a functional one (in cystic fibrosis) (see below). The issues are more complex for diseases that are not due to single gene defects, but genetic susceptibility factors are being identified.

A series of studies on asthma have now confirmed that several gene loci are involved in susceptibility to atopy and occupational asthma. A polymorphism for the gene encoding the ß subunit of the high affinity receptor for IgE (FcER1-ß) on chromosome 11q has been shown to be associated with atopy.⁷ In recent studies the same group of researchers has now shown that the transmission of the polymorphism is maternal.⁸ In this regard, two specific amino acid substitutions (at positions 181 and 183) of the IgE receptor ß chain (isoleucine to leucine; valine to leucine respectively) were found to be associated with atopy and high serum IgE concentration when maternally transmitted. The importance of this polymorphism in atopy and asthma can be estimated only by investigation of its frequency and expression in community populations.

Marsh et al have found an association between high serum IgE concentration and five markers on chromosome 5q in the region of the interleukin 4 gene cluster: TH2 driven immune responses which are now known to be important in the eosinophilic bronchitis of asthma are interleukin 4 dependent.⁹

Several studies have shown more specific gene relations between the antigens in the class II major histocompatibility complex responsible for the recognition of non-self and asthma. An HLA-DR2 linked haplotype was found to be associated with patients with asthma, but not rhinitis, caused by ragweed pollen¹⁰; alleles at the DQ locus (QB1*0503; DQB1*0201/0301) related to susceptibility to occupational asthma due to exposure to isocyanate whereas different DQ related haplotypes conferred protection; and predisposition to specific IgE induced by acid anhydride was associated with HLA-DR3 in another study of occupational hypersensitivity.*RF 11, 11a*

These studies, taken together with work that has shown a relation between class II major histocompatibility complex and diffuse lung disease in systemic sclerosis and rheumatoid arthritis, provide evidence of immunogenetic factors that predispose to chronic pulmonary inflammatory disorders. Although the mechanisms of chronic inflammation are complex, recognition of these genetically determined predispositions can lead to identification of at risk groups and focus studies on the inductive stages of disease, particularly when concepts of causation become clearer (see above). Future strategies for managing asthma will involve studies of polymorphisms and their relation to disease in populations (molecular epidemiology) and evaluation of outcome to determine the efficacy of any intervention.

Cystic fibrosis

Although rates of death from cystic fibrosis have improved considerably over recent years, largely owing to better treatment of lung infection and better nutrition, the average life span remains only about 30 years, with most patients dying from lung disease. Two new treatment approaches hold promise: aerosolised human recombinant DNase and gene therapy.

AEROSOLISED HUMAN RECOMBINANT DNASE

Airway secretions are viscous in cystic fibrosis; a significant component of the viscosity is DNA from inflammatory cells which are recruited to the bronchi. Endogenous DNases normally degrade DNA in extracellular sites but in cystic fibrosis the burden is too great. Against this background, human recombinant DNase was developed for administration with a nebuliser to patients with cystic fibrosis. Previous studies in vitro and pilot studies in vivo suggested that the approach was sound.¹² The findings of a multicentre, randomised, double blind, placebo controlled study in which 968 patients were enrolled provide further support for the use of the drug in cystic fibrosis. Comparisons of once and twice daily administrations of DNase for 24 weeks showed that the rate of exacerbations decreased, the measurements of forced expiratory volume in one second improved by on average 6%, and the drug was well tolerated.¹³ The findings have important implications. The cost effectiveness of human recombinant DNase is unknown--the cost of recombinant products is high--and long term efficacy must be shown through evaluative studies of outcomes.¹⁴ Current evidence, however, seems to support the use of DNase.

GENE THERAPY

Gene therapy involves the correction of an underlying pathophysiological defect through the transfer of genes. Since the gene for cystic fibrosis was first identified and cloned in 1989, remarkable strides have been made in applying molecular technology to the gene transfer for cystic fibrosis in humans. The gene is transferred in a "carrier" (in either a cationic lipid envelope known as a liposome or in an adenovirus). Adenovirus vectors are constructed such that the E1 region of the genome (needed for viral replication) is deleted and have been used to transfer a functional gene capable of protein production and correction of the cell's functional deficiency in vitro^{15 16}; they have also been transferred efficiently in vivo.^{17 18 19 20}

These approaches are not without complications: the adenovirus can stimulate an inflammatory response due, at least in part, to local anamnestic immune responses to adenoviral protein.^{21 22} More recently, Caplen et al have used cationic liposomes to transfer the gene for cystic fibrosis to human nasal epithelium.²³ The deficit was partly restored temporarily, but, importantly, the transfer did not provoke a local inflammatory response.

Gene transfer will clearly be an important future therapeutic option, although much is still to be learned about the targeting and transfection efficiency of the vector and increasing the duration of gene expression.^{24 25}

Adult respiratory distress syndrome

Overall mortality from acute lung injury severe enough to result in the adult respiratory distress syndrome is roughly 50%, although some recent studies show a figure nearer 40%. This depressing situation has stimulated considerable research aimed at improving mechanical ventilation or oxygenation through extracorporeal devices and at reversing or modulating the inflammatory responses that amplify local injury and provoke subsequent fibrosis.

The findings of many of these studies have been disappointing, including the preliminary results from an international study of exogenous surfactant. Although the final report has not been published, a large international, randomised, placebo controlled trial of aerosolised surfactant in the adult respiratory distress syndrome induced by sepsis was reported to have been abandoned because of lack of efficacy.²⁶

In contrast, a study of the use of human recombinant interleukin 1 receptor antagonist was more positive.²⁷ Interleukin 1 is a proinflammatory cytokine released by several cell types, including the alveolar macrophage, during the early phases of inflammation. The use of a recombinant compound that inhibits interleukin 1 binding to its receptor is logical. Results from this placebo controlled multicentre study showed that interleukin 1 receptor antagonist reduced the death rate from 44% to 16% in patients receiving the highest test dose (133 mg/h) of active compound at 28 days. Further, larger clinical studies are needed to confirm this encouraging observation.

Imaging

Computed tomography, particularly with a high spatial resolution bone algorithm, has been used increasingly over the past 5-10 years to define lung disease with greater precision than is possible with conventional imaging techniques. Previous studies have concentrated on descriptive series of disease patterns and have concluded that high resolution computed tomography is more sensitive and specific than chest radiography in diagnosing diffuse lung disease. The result is that computed tomography has now replaced lung biopsy in the diagnosis and staging of selected cases of diffuse lung disease, and this is highly cost effective.

A recent study from Remy-Jardin et al of a large group of patients with rheumatoid arthritis confirmed that apparently occult and potentially life threatening disease can be identified and that computed tomography can readily discriminate the different forms of lung disease that may be present in this condition.²⁸ Further prospective studies on prognosis similar to those published on systemic sclerosis^{29 30} are needed to assess the prognostic value of computed tomography in rheumatoid arthritis and other rheumatological diseases.

LOW DOSE COMPUTED TOMOGRAPHY

Despite the major advance in imaging information provided by computed tomography, radiation burden has always been a concern. Muller's group in Vancouver has shown that low dose, thin section computed tomography can provide images that compare well to conventional dose computed tomography in diagnosis and are superior to chest radiographs.³¹ A high confidence rating for diagnosis was obtained in only 42% of radiographs but in 61% of low dose and 63% of conventional dose computed tomograms.

FUNCTIONAL ASSESSMENT

Other recent studies of computed tomography of the lung have continued to move from anatomical description to functional assessment, including evaluation of activity and prognosis. In sarcoidosis, unlike the correlations in fibrosing alveolitis, computed tomograms do not predict outcome, although some patterns--most notably, "ground glass" attenuation--reflect functional impairment.³²

Airways diseases can also be assessed functionally with computed tomography. In an investigation of 70 patients producing chronic purulent sputum, areas of decreased attenuation, indicative of small airways disease (fig 1), were seen in areas of lung with severe bronchiectasis but also in 69 of 406 lobar observations in areas of lung with no bronchiectasis (fig 2).³³ This suggests that small airways disease may be an early feature of bronchiectasis, which leads to more progressive injury and bronchiolar distortion. Longer term studies are needed to clarify this, but if confirmed as an early marker of disease, these changes shown with computed tomography could form the basis of the design of studies to prevent progression of disease.

View larger version (62K): [in this window] [in a new window]   FIG 1--Large plugs of mucus in bronchiectatic airways in periphery of lower lobe; surrounding lung is of lower density because of reduced ventilation and thus perfusion (reproduced with permission33)

View larger version (48K): [in this window] [in a new window]   FIG 2--Top: Computed tomogram obtained during full inspiration shows mild bronchiectasis confined to posterobasal segment of left lower lobe and areas of minimally decreased attenuation (reproduced with permission33). Bottom: Computed tomogram obtained at end of expiration shows areas of decreased attenuation in left lower lobe and air trapping in a few secondary pulmonary lobules in right lower lobe (reproduced with permission33)

OTHER IMAGING

Although conventional computed tomography is now well etablished, spiral computed tomography is rapidly becoming the standard way to image the thorax.³⁴ The advantages of truly contiguous sections is that totally seamless reconstructions are possible that may ultimately be used, for example, for virtual reality bronchoscopy imaging.

Magnetic resonance imaging continues to wait in the wings. The tantalising prospect of a non-ionising radiation means of imaging the lung parenchyma is hindered by formidable technical problems in producing satisfactory images, although magnetic resonance imaging is as good as computed tomography in staging lung cancer.

            Recent advances in respiratory medicine
--------------------------------------------------------------------------------
* Susceptibility to atopy and occupational asthma has been shown to
involve gene loci: interrelations between such predispositions and environmental
triggers are likely to provide insight into the causation of asthma
* Social factors are important determinants of increased rates of death
from asthma
* The successful transfer of genes to human epithelium is a major breakthrough
for the long term management of cystic fibrosis
* The introduction of recombinant DNase improves lung function and is
likely to increase life span in patients with cystic fibrosis
* Cytokine antagonists reduce death rates from the adult respiratory
distress syndrome
* High resolution computed tomography is transforming discrimination
and prognosis in different forms of diffuse lung disease and can assess
functional airways disease
* Spiral computed tomography produces seamless reconstructions of
pulmonary structure that may herald virtual reality imaging

Conclusion

The lung has several unique attributes. Combined, these have enabled striking advances in management to be made by harnessing huge technological advances to clinical problems, an approach which must continue if we are to use our limited health care resources most effectively and efficiently.

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[Abstract]
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