BMJ 1999;318:171-176 ( 16 January )

Clinical review

Recent advances

Pulmonary medicine

Nicolas Roche, assistant in pulmonary medicine. 

Service de Pneumologie, Hôpital Ambroise Paré, F-92104 Boulogne, France

Correspondence to: Dr Roche, Imperial College School of Medicine, National Heart and Lung Institute, London SW3 6LY bnroche{at}club-internet.fr

Respiratory medicine covers a great variety of disorders that are common in general clinical practice, and many important papers have been published on these illnesses in the past few years. Since the volume of published articles makes it almost impossible for doctors to be informed of all recent developments in medicine, this review aims to provide practical information on recent scientific evidence that may change practice in pulmonary medicine.


Summary points

Long acting bronchodilators should not be prescribed without inhaled corticosteroids in asthma
When asthma symptoms persist despite regular use of inhaled corticosteroids, beta  agonists or theophylline may be preferred to increasing the dose of corticosteroids
Oral leukotriene modulators may be useful for patients who do not respond adequately to usual doses of corticosteroids
Pulmonary rehabilitation (including exercise reconditioning) is effective in breathless patients at virtually all stages of chronic obstructive pulmonary disease
Lung volume reduction surgery is also effective in patients with emphysema who have severe disability due to severe airway obstruction and lung hyperinflation
Prediction rules have been developed to identify patients who should be referred to hospital with community acquired pneumonia
Directly observed and fixed dose combination therapy are more cost effective than conventional treatment of active tuberculosis



    Methods
Top
Methods
Asthma
Chronic obstructive pulmonary...
Thromboembolic disease
Community acquired pneumonia
Tuberculosis: is directly...
References

The large number of publications each year makes a classic Medline search unsuitable for a literature review on "recent advances" in a given specialty. However, database searches do show the number of papers published on selected topics, which may reflect the amount of research and new information (table 1).


                              
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Table 1. Results of Medline search for articles published between February 1997 and February 1998 in some areas of pulmonary medicine

The references in this review have been identified by regular reading of the following journals: American Journal of Respiratory and Critical Care Medicine, Chest, Thorax, Respiratory Medicine, Respiration, Respirology, Journal of Aerosol Medicine, Revue des Maladies Respiratoires, Nature, New England Journal of Medicine, Lancet, BMJ, Annals of Internal Medicine, Archives of Internal Medicine, Annales de Medecine Interne. To be selected articles had to fulfil all the following criteria: (a) the topic is important in daily clinical practice; (b) the methods used are adequate; (c) the conclusions are supported by the data presented; and (d) the results are informative and original and should affect daily clinical practice or greatly increase our knowledge.

Since many papers fulfilled these criteria the final selection had to be partly subjective and arbitrary. However, I hope this review will provide useful answers to some relevant questions in clinical pulmonary medicine.

    Asthma
Top
Methods
Asthma
Chronic obstructive pulmonary...
Thromboembolic disease
Community acquired pneumonia
Tuberculosis: is directly...
References

How can deaths from asthma be avoided?
Although death from asthma is uncommon (about 5000 deaths occurred among 10 million asthmatic patients in the United States in 1991), most deaths are thought to be avoidable by proper identification and care of patients at risk. Indeed, true sudden asphyxic asthma is very rare, and most patients who die of asthma have had a final episode that lasted more than 12 hours, which should be sufficient for adequate treatments to be effective. Moreover, many studies have shown a relation between asthma deaths and previously inadequate assessment or treatment (for example, insufficient use of inhaled corticosteroids). McFadden and Warren listed the risk factors for death from asthma (box), and special attention should be given to patients who have one or more of these factors.1 All asthmatic patients should have their risk assessed, and those at risk should have more frequent assessments of symptoms and lung function to allow early changes in treatment and increased follow up when asthma instability develops. Patients should also be given a self management plan based on symptoms or peak expiratory flow, or both, for emergency situations. 2 3 Similarly, a written emergency protocol for asthma care should be available in every emergency ward.


Risk factors for death from asthma1

Medical history

Previous near fatal episode of asthma

Previous abrupt development of poorly responsive   and quickly progressive symptoms

Previous normocapnic or hypercapnic asthma attack

Poor perception of bronchial obstruction (assessed by    discrepancies between symptoms and lung function tests)

Clear circadian variations in lung function (assessed by   peak expiratory flow)

Frequent hospital admissions or emergency visits

Recent increase in the frequency of nocturnal   awakenings or daytime dyspnoea or wheezing

Psychosocial instability, poor comprehension, poor   compliance

   Features of the current episode

Severe airway obstruction

Poor (<40%) improvement after the first   administration of sympathomimetic bronchodilators

Severe hypoxaemia (oxygen saturation<90%)

Normocapnia or hypercapnia

Metabolic acidosis

Is there a role for monitoring airway inflammation?
Morbidity and mortality from asthma should be reduced if treatment is closely adapted to the degree of airway inflammation. This could be made possible by some new non-invasive tools which include analysis of induced sputum (cell content or concentration of inflammatory mediators), measurement of exhaled nitric oxide or hydrogen peroxide, and measurement of serum or urinary eosinophil products such as eosinophil cationic protein or eosinophil protein X.4-6 Although these markers have been shown to reflect (at least partly) the degree of airway inflammation, the clinical usefulness of the additional information they provide remains unclear and needs further investigation.

Choosing the best strategy for maintenance treatment
Inhaled anti-inflammatory drugs (corticosteroids or cromoglycate and nedocromil) are the first line components of maintenance treatment in asthma according to all guidelines.7 Long acting inhaled beta  agonists are also highly effective at preventing symptoms and controlling exercise induced and nocturnal asthma. However, in a randomised study of 67 children with mild to moderate asthma beclomethasone (200 µg twice daily) administered for 1 year was more effective than salmeterol (50 µg twice daily) in terms of lung function, bronchial hyperresponsiveness, and rate of exacerbations.8 Thus, inhaled long acting beta  agonists should not be used as monotherapy for long term treatment of asthma. Similarly, theophylline was less effective and less well tolerated than inhaled corticosteroids in 747 adults and children with moderate to severe asthma.9

Several large, randomised, double blind, placebo controlled trials have examined treatments for patients in whom asthma symptoms persist despite low dose inhaled corticosteroids. These studies concluded that adding an inhaled long acting beta  agonist (eformoterol 12 µg or salmeterol 50 µg twice daily) or theophylline (250 or 375 mg/day) was as effective as or better than increasing the dose of inhaled corticosteroids in terms of symptoms, lung function, and rate of exacerbations. 10 11 Addition of inhaled long acting beta  agonists or theophylline may be preferable in these patients as high doses of inhaled corticosteroids (>1000 µg/day) have been associated with an increased risk of skin bruising, cataracts, lower adrenocortical function, and lower bone density, although the last two effects have not yet been shown to be clinically important. 12 13

Finally, a new class of anti-inflammatory drugs, leukotriene modulators, has recently become available and may change the approach to maintenance treatment for asthma.14 Several findings point to leukotrienes as important mediators in asthma. Firstly, leukotriene B4 attracts neutrophils and activates T lymphocytes in the airways, and cysteinyl leukotrienes are potent bronchoconstrictors and increase vascular permeability, mucus secretion, and bronchial hyperresponsiveness to methacholine or histamine. Secondly, asthmatic subjects are more sensitive to inhaled exogenous leukotrienes than controls. Thirdly, the leukotriene concentrations in the urine, serum, and respiratory secretions of asthmatic patients increase during exacerbations or after allergen challenge.14

The effects of leukotrienes can be modulated by blocking their synthesis or their receptors. Drugs that inhibit 5-lipo-oxygenase, such as zileuton, or antagonise cysteinyl-leukotriene receptors, such as zafirlukast and montelukast, have been shown to prevent bronchospasm induced by antigen, aspirin, or exercise.14 Several randomised controlled studies also showed that regular use improves lung function, reduces bronchial hyperresponsiveness, and decreases symptoms and use of bronchodilators. Leukotriene receptor antagonists have also been shown to allow a reduction in the dose or even withdrawal of inhaled corticosteroids.14 Some leukotriene modulators have already been approved for asthma maintenance in several countries, and the US National Heart Lung and Blood Institute expert panel on asthma classifies them as alternatives to inhaled corticosteroids in patients with mild persistent asthma. Inhaled corticosteroids remain the preferred treatment, but leukotriene modifiers may be indicated when inhaled corticosteroids do not control asthma or when high doses are required.14 They could also be useful in patients who cannot tolerate aspirin or those with exercise induced asthma. Finally, since leukotriene modulators are taken orally, they may be useful in patients who cannot use inhalation devices correctly. Increases in the use of these drugs and in published clinical trials will help to define their role more precisely.

    Chronic obstructive pulmonary disease
Top
Methods
Asthma
Chronic obstructive pulmonary...
Thromboembolic disease
Community acquired pneumonia
Tuberculosis: is directly...
References

Chronic obstructive pulmonary disease is the fourth or fifth highest cause of death in developed countries.15 Treatment has been expensive because of the high rate and length of hospital admissions in elderly patients.16 Treatment should be directed at increasing survival, improving symptoms, preventing complications, and accelerating recovery when exacerbations occur. Only two interventions have been shown to increase survival of smokers who develop chronic obstructive pulmonary disease. The first is stopping smoking, which is beneficial at all stages of the disease. Nicotine patches roughly double success rates and have a lower cost per quality adjusted life year gained than other widely used preventive measures such as screening for hypertension.17 The second is long term oxygen therapy, which increases life expectancy of patients with chronic respiratory failure. The main goal of other interventions is to relieve symptoms.

How can dyspnoea be relieved?
Airway obstruction is generally not reversible in chronic obstructive pulmonary disease, but bronchodilators (including inhaled short and long acting beta  agonists and anticholinergic drugs) may reduce dyspnoea and improve quality of life even in the absence of significant changes in spirometric variables. 18 19 Dyspnoea may indeed be due to many factors other than airway obstruction, such as impaired gas exchange, thoracic hyperinflation, impaired ventilatory mechanics and diaphragmatic function, loss of elastic lung recoil, respiratory and peripheral muscle weakness and deconditioning, and impaired nutritional or psychological state.

Multidisciplinary rehabilitation programmes significantly improve symptoms, activities of daily living, and quality of life in symptomatic patients with chronic obstructive pulmonary disease even when results of lung function tests remain unchanged.20 These programmes often last eight weeks with three sessions of 90 minutes each week. They include help with stopping smoking, optimisation of drug treatment, health education, psychosocial and nutritional support, chest physiotherapy and breathing exercises, and exercise reconditioning (one of the main components). Since pulmonary rehabilitation helps virtually all patients with chronic obstructive pulmonary disease who experience dyspnoea21 it is difficult to determine which patients should be treated first when resources are limited. The degree of impairment in daily living should be the main selection criterion, but there is no recommended threshold.22

Another intervention that is attracting increasing interest is lung reduction surgery. This has been shown to improve dyspnoea, exercise tolerance, and quality of life through effects on lung function, dynamic hyperinflation, elastic lung recoil, ventilatory mechanics, and respiratory muscle function.23-26 However, no randomised trials or cost effectiveness analyses have been reported, and follow up rarely exceeds one year in available studies so it is difficult to define which patients will benefit most.27 Pathophysiological considerations and published clinical trials suggest that surgery may be beneficial in highly motivated patients with emphysema who have severe airflow obstruction and lung hyperinflation and are severely disabled despite stopping smoking, optimal drug treatment, and pulmonary rehabilitation.27 The chances of success may be greater when emphysema is heterogeneous, being most severe in the upper lobe.27 Surgery should probably not be used for patients with very severe disease---that is, those with an arterial carbon dioxide pressure above 6 kPa and those who cannot walk more than 200 m in 6 minutes.26

What are the effects of inhaled and oral corticosteroids?
Although corticosteroids greatly reduce airway inflammation in asthma, they have little effect on sputum indices of inflammation in chronic obstructive pulmonary disease. Patients with histopathological features of asthma (eosinophilic inflammation), however, do improve after a short course of oral corticosteroids. 28 29 This may partly explain why studies on inhaled corticosteroids in chronic obstructive pulmonary disease have given conflicting results. A recent placebo controlled randomised trial assessed the effect of 500 µg of inhaled fluticasone twice daily in 281 patients with chronic obstructive pulmonary disease over six months.30 To minimise chances of including patients with asthma, bronchodilator reversibility had to be less than 15%. Fluticasone produced a mild but significant improvement in symptoms, lung function, and six minute walking distance and reduced the number of moderate to severe exacerbations.30 However, long term trials have found that inhaled corticosteroids are beneficial for only three to six months. Therefore, although bronchodilators are widely prescribed for chronic obstructive pulmonary disease, their role in long term management remains debated. Moreover, there are no consistent data on the clinical and functional characteristics of responders, which is probably because of the relatively small number of people studied. Publication of the complete results of the European study of corticosteroids in chronic obstructive pulmonary disease (EUROSCOP), in which over 900 patients received budesonide or placebo for three years, may provide more information.

Oral corticosteroids are also widely used in acute exacerbations of chronic obstructive pulmonary disease, although their effect has been assessed in few studies. A randomised double blind study recently showed that a nine day treatment with tapering dose of oral prednisone (60 mg for three days, 40 mg for three days, and 20 mg for three days) accelerates recovery in terms of lung function and gas exchange and reduces the rate of treatment failures (0/13 v 8/14 in placebo group).31

    Thromboembolic disease
Top
Methods
Asthma
Chronic obstructive pulmonary...
Thromboembolic disease
Community acquired pneumonia
Tuberculosis: is directly...
References

Deep vein thrombosis and pulmonary embolism are common with a cumulative probability of 10.7% by the age of 80 years.32 Thus, both diagnosis and treatment of thromboembolic disease are important issues in routine practice. Diagnosis is difficult as the clinical features have a poor predictive value.

Is it possible to rule out thromboembolic events safely by simple investigations?
A simplified compression ultrasonography technique has been described recently for deep vein thrombosis in which imaging is limited to the deep veins at the popliteal fossa and groin. Imaging has to be repeated after one week to ensure that no proximally extending thrombus of the calf veins is missed. The reliability of this technique has been tested in two large studies of patients with a suspected first deep vein thrombosis. Anticoagulation was withheld if the two ultrasound examinations gave negative results, and the patients were followed for three to six months. 33 34 Both studies confirmed that only about a fifth of patients with suspected deep vein thrombosis have one detected. In patients with negative results the risk of thromboembolism was very low (0.6%), which confirms the high negative predictive value of this strategy.

The negative predictive value of a D-dimer concentration below 500 µg/l has also been evaluated in 671 patients with suspected acute pulmonary embolism, in whom the prevalence of pulmonary embolism was 29%.35 An embolism was detected in only one of the 198 patients with a D-dimer concentration below the threshold. In the remaining 197 patients anticoagulation was withheld and no thromboembolic event was recorded during the three month follow up. Similar results have been found in patients with suspected deep vein thrombosis, in whom a normal D-dimer concentration had a negative predictive value of 97%.36 These high negative predictive values suggest that the test will be useful in clinical practice despite its poor specificity (40%).

Can the treatment of acute thromboembolism be simplified?
In 1996 two large randomised trials showed that home treatment with low molecular weight heparin is at least as safe and effective as unfractionated heparin for proximal deep vein thrombosis. 37 38 Since these trials excluded patients with suspected pulmonary embolism or previous thromboembolic events, two further studies examined the safety and efficacy of low molecular weight heparin in unselected patients with acute thromboembolic events. 39 40 Both found that fixed dose subcutaneous low molecular weight heparin was as effective and as safe as adjusted dose unfractionated heparin (table 2). The above trials all used twice daily doses, but a trial of a once daily fixed dose of tinzaparin in 612 patients with acute pulmonary embolism also showed it was as safe and as effective as unfractionated heparin (table 2).41 Despite the lack of rigorous cost effectiveness data, subcutaneous, fixed dose, low molecular weight heparins are likely to be used increasingly for acute deep vein thrombosis and pulmonary embolism.


                              
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Table 2. Safety and efficacy of fixed dose low molecular weight heparins compared with unfractionated heparins in deep vein thrombosis and pulmonary embolism: data from three randomised trials


                              
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Table 3. Point scoring system for hospital referral of patients with community acquired pneumonia (adapted from Fine et al42)



    Community acquired pneumonia
Top
Methods
Asthma
Chronic obstructive pulmonary...
Thromboembolic disease
Community acquired pneumonia
Tuberculosis: is directly...
References

How can we determine which patients should be referred to hospital?
Community acquired pneumonia is an important cause of hospital stays, but admission rates vary greatly among studies and doctors suggesting the need for reliable and widely recognised predictors of poor outcome. A study of over 50 000 patients derived and validated criteria for predicting prognosis of community acquired pneumonia (table 3).42 Twenty criteria were used to define five risk classes, and the authors found that a strategy of outpatient care for patients in classes I and II, brief inpatient observation for class III, and traditional inpatient care for classes IV and V would reduce safely the number of hospital stays by about one third.42 Although the scoring system may be too complex for routine use, it may help make difficult decisions about referral.

Should elderly people be vaccinated against Streptococcus pneumoniae?
Community acquired pneumonia is relatively common in elderly people with up to 26 cases per 1000 people over 65 each year. Mortality is about 19% and up to 67% of cases require hospital admission.43 Streptococcus pneumoniae is one of the commonest pathogens and can cause potentially life threatening bacteriaemia. Several studies have shown that the 23 valent pneumococcal vaccine prevents pneumococcal bacteraemia in high risk patients. However, trials of the vaccine in lower risk subjects have given conflicting results. 44 45 A Swedish study of 691 middle aged and elderly patients (of whom two thirds were older than 65) who had been admitted to hospital with pneumonia found the vaccine had no effect on the rate of recurrence of pneumonia (including pneumococcal pneumonia), which was 16% to 19% during the 2.5 year follow up.44 This lack of effect was observed even in patients with coexisting chronic illnesses. In a Finnish trial of 4213 patients older than 60, 34% of whom had diseases which put them at higher risk for contracting pneumonia, the vaccine had a 59% efficacy for prevention of pneumonia.45 An American economic analysis found that vaccination of all patients older than 65 would be cost effective, although the analysis may have overestimated the protective effect of the vaccine.46 These data suggest that pneumococcal vaccination may be indicated in elderly people with chronic illnesses.

    Tuberculosis: is directly observed therapy cost effective?
Top
Methods
Asthma
Chronic obstructive pulmonary...
Thromboembolic disease
Community acquired pneumonia
Tuberculosis: is directly...
References

Treatment of active tuberculosis gives cure rates above 95% provided that the strain of Mycobacterium tuberculosis is not multidrug resistant and that compliance is adequate. Non-adherence to treatment may decrease cure rates to 79% and increase the prevalence of multidrug resistant strains.47 In the United States the Center for Disease Control and Prevention has recommended the use of directly observed therapy whenever possible. Two studies based on decision analysis models have verified that this form of treatment is more cost effective than self administered treatment. 47 48 One of these economic analyses also showed that fixed dose combination therapy, which decreases the daily number of tablets and the risk of emergence of resistant strains with poor compliance, is also more cost effective than conventional treatment.48 Thus, directly observed or fixed dose combination therapy should be considered in virtually all patients with active tuberculosis, at least when there is a risk of non-compliance.

    References
Top
Methods
Asthma
Chronic obstructive pulmonary...
Thromboembolic disease
Community acquired pneumonia
Tuberculosis: is directly...
References

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  2. Cowie RL, Revitt SG, Underwood MF, Field SK. The effect of a peak flow-based action plan in the prevention of exacerbations of asthma. Chest 1997; 112: 1534-1538[Abstract/Free Full Text].
  3. Turner MO, Taylor D, Bennett R, Fitzgerald JM. A randomized trial comparing peak expiratory flow and symptom self-management plans for patients with asthma attending a primary care clinic. Am J Respir Crit Care Med 1998; 157: 540-546[Abstract/Free Full Text].
  4. Pavord ID, Pizzichini MM, Pizzichini E, Hargreave FE. The use of induced sputum to investigate airway inflammation. Thorax 1997; 52: 498-501[Medline].
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  8. Verberne AA, Frost C, Roorda RJ, van der Laag H, Kerrebijn KF. One year treatment with salmeterol compared with beclomethasone in children with asthma. The Dutch Paediatric Asthma Study Group. Am J Respir Crit Care Med 1997; 156: 688-695[Abstract/Free Full Text].
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  11. Pauwels RA, Lofdahl CG, Postma DS, Tattersfield AE, O'Bryne P, Barnes PJ, et al. Effect of inhaled formoterol and budesonide on exacerbations of asthma. Formoterol and Corticosteroids Establishing Therapy (FACET) International Study Group. N Engl J Med 1997; 337: 1405-1411[Abstract/Free Full Text].
  12. Cumming RG, Mitchell P, Leeder SR. Use of inhaled corticosteroids and the risk of cataracts. N Engl J Med 1997; 337: 8-14[Abstract/Free Full Text].
  13. Roy A, Leblanc C, Paquette L, Ghezzo H, Cote J, Cartier A, et al. Skin bruising in asthmatic subjects treated with high doses of inhaled steroids: frequency and association with adrenal function. Eur Respir J 1996; 9: 226-231[Abstract].
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  15. Mannino DM, Brown C, Giovino GA. Obstructive lung disease deaths in the United States from 1979 through 1993. An analysis using multiple-cause mortality data. Am J Respir Crit Care Med 1997; 156: 814-818[Abstract/Free Full Text].
  16. Cydulka RK, McFadden Jr ER, Emerman CL, Sivinski LD, Pisanelli W, Rimm AA. Patterns of hospitalization in elderly patients with asthma and chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1997; 156: 1807-1812[Abstract/Free Full Text].
  17. Fiscella K, Franks P. Cost-effectiveness of the transdermal nicotine patch as an adjunct to physicians' smoking cessation counseling. JAMA 1996; 275: 1247-1251[Abstract].
  18. Jones PW, Bosh TK. Quality of life changes in COPD patients treated with salmeterol. Am J Respir Crit Care Med 1997; 155: 1283-1289[Abstract].
  19. Ramirez-Venegas A, Ward J, Lentine T, Mahler DA. Salmeterol reduces dyspnea and improves lung function in patients with COPD. Chest 1997; 112: 336-340[Abstract/Free Full Text].
  20. Gosselink R, Troosters T, Decramer M. Exercise training in COPD patients: the basic questions. Eur Respir J 1997; 10: 2884-2891[Abstract].
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  23. Keller CA, Ruppel G, Hibbett A, Osterloh J, Naunheim KS. Thoracoscopic lung volume reduction surgery reduces dyspnea and improves exercise capacity in patients with emphysema. Am J Respir Crit Care Med 1997; 156: 60-67[Abstract/Free Full Text].
  24. Tschernko EM, Wisser W, Wanke T, Rajek MA, Kirtzinger M, Lahrmann H, et al. Changes in ventilatory mechanics and diaphragmatic function after lung volume reduction surgery in patients with COPD. Thorax 1997; 52: 545-550[Abstract].
  25. Martinez FJ, de Oca MM, Whyte RI, Stetz J, Gay SE, Celli BR. Lung-volume reduction improves dyspnea, dynamic hyperinflation, and respiratory muscle function. Am J Respir Crit Care Med 1997; 155: 1984-1990[Abstract].
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  27. Russi EW, Stammberger U, Weder W. Lung volume reduction surgery for emphysema. Eur Respir J 1997; 10: 208-218[Abstract].
  28. Chanez P, Vignola AM, O'Shaunessy T, Enander I, Li D, Jeffery PK, et al. Corticosteroid reversibility in COPD is related to features of asthma. Am J Respir Crit Care Med 1997; 155: 1529-1534[Abstract].
  29. Keatings V, Jatakanon A, Worsdell Y, Barnes P. Effects of inhaled and oral glucocorticoids on inflammatory indices in asthma and COPD. Am J Respir Crit Care Med 1997; 155: 548.
  30. Paggiaro PL, Dahle R, Bakran I, Frith L, Hollingworth K, Efthimiou J. Multicentre randomised placebo-controlled trial of inhaled fluticasone propionate in patients with chronic obstructive pulmonary disease. International COPD Study Group. Lancet 1998; 351: 773-780[Medline].
  31. Thompson WH, Nielson CP, Carvalho P, Charan NB, Crowley JJ. Controlled trial of oral prednisone in outpatients with acute COPD exacerbation. Am J Respir Crit Care Med 1996; 154: 407-412[Abstract].
  32. Hansson PO, Welin L, Tibblin G, Eriksson H. Deep vein thrombosis and pulmonary embolism in the general population. The study of men born in 1913. Arch Intern Med 1997; 157: 1665-1670[Abstract].
  33. Birdwell BG, Raskob GE, Whitsett TL, Durica SS, Comp PC, George JN, et al. The clinical validity of normal compression ultrasonography in outpatients suspected of having deep venous thrombosis. Ann Intern Med 1998; 128: 1-7[Abstract/Free Full Text].
  34. Cogo A, Lensing AW, Koopman MM, Piovella F, Siragusa S, Wells PS, et al. Compression ultrasonography for diagnostic management of patients with clinically suspected deep vein thrombosis: prospective cohort study. BMJ 1998; 316: 17-20[Abstract/Free Full Text].
  35. Perrier A, Desmarais S, Goehring C, de Moerloose P, Morabia A, Unger PF, et al. D-dimer testing for suspected pulmonary embolism in outpatients. Am J Respir Crit Care Med 1997; 156: 492-496[Abstract/Free Full Text].
  36. Ginsberg JS, Kearon C, Douketis J, Turpie AG, Brill-Edwards P, Stevens P, et al. The use of D-dimer testing and impedance plethysmographic examination in patients with clinical indications of deep vein thrombosis. Arch Intern Med 1997; 157: 1077-1081[Abstract].
  37. Koopman MMW, Prandoni P, Piovella F, Ockelford PA, Brandjes DPM, van der Meer J, et al. Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low-molecular-weight heparin administered at home. N Engl J Med 1996; 334: 682-687[Abstract/Free Full Text].
  38. Levine M, Gent M, Hirsh J, Leclerc J, Anderson D, Weitz J, et al. A comparison of low-molecular-weight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep-vein thrombosis. N Engl J Med 1996; 334: 677-681[Abstract/Free Full Text].
  39. Decousus H, Leizorovicz A, Parent F, Page Y, Tardy B, Girard P, et al. A clinical trial of vena caval filters in the prevention of pulmonary embolism in patients with proximal deep-vein thrombosis. Prevention du Risque d'Embolie Pulmonaire par Interruption Cave Study Group. N Engl J Med 1998; 338: 409-415[Abstract/Free Full Text].
  40. Columbus Investigators. Low-molecular-weight heparin in the treatment of patients with venous thromboembolism. N Engl J Med 1997; 337: 657-662[Abstract/Free Full Text].
  41. Simonneau G, Sors H, Charbonnier B, Page Y, Laaban JP, Azarian R, et al. A comparison of low-molecular-weight heparin with unfractionated heparin for acute pulmonary embolism. The THESEE Study Group. Tinzaparine ou Heparine Standard: Evaluations dans l'Embolie Pulmonaire. N Engl J Med 1997; 337: 663-669[Abstract/Free Full Text].
  42. Fine MJ, Auble TE, Yealy DM, Hanusa BH, Weissfeld LA, Singer DE, et al. A prediction rule to identify low-risk patients with community-acquired pneumonia. N Engl J Med 1997; 336: 243-250[Abstract/Free Full Text].
  43. Jokinen C, Heiskanen L, Juvonen H, Kallinen S, Larkola K, Korppi M, et al. Incidence of community-acquired pneumonia in the population of four municipalities in eastern Finland. Am J Epidemiol 1993; 137: 977-988[Abstract/Free Full Text].
  44. Ortqvist A, Hedlund J, Burman LA, Elbel E, Hofer M, Leinonen M, et al. Randomised trial of 23-valent pneumococcal capsular polysaccharide vaccine in prevention of pneumonia in middle-aged and elderly people. Swedish Pneumococcal Vaccination Study Group. Lancet 1998; 351: 399-403[Medline].
  45. Koivula I, Sten M, Leinonen M, Makela PH. Clinical efficacy of pneumococcal vaccine in the elderly: a randomized, single-blind population-based trial. Am J Med 1997; 103: 281-290[Medline].
  46. Sisk JE, Moskowitz AJ, Whang W, Lin SD, Fedson DS, McBean AM, et al. Cost-effectiveness of vaccination against pneumococcal bacteremia among elderly people. JAMA 1997; 278: 1333-1339[Abstract].
  47. Burman WJ, Dalton CB, Cohn DL, Butler JR, Reves RR. A cost-effectiveness analysis of directly observed therapy vs self- administered therapy for treatment of tuberculosis. Chest 1997; 112: 63-70[Abstract/Free Full Text].
  48. Moore RD, Chaulk CP, Griffiths R, Cavalcante S, Chaisson RE. Cost-effectiveness of directly observed versus self-administered therapy for tuberculosis. Am J Respir Crit Care Med 1996; 154: 1013-1019[Abstract].

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