European Respiratory Society
Pulmonary Manifestations of Systemic Diseases

Pulmonary manifestations of systemic diseases remain very interesting disease entities. However, they are usually not very well known by the treating physician. Therefore, in the present Monograph, the editors have tried to gather a compilation of interesting pulmonary manifestations of very different disease entities, such as collagen vascular diseases and vasculitis syndromes, but also pulmonary involvement in renal, hepatic, gastrointestinal, neuromuscular, endocrine and metabolic, cardiovascular, immunodeficiency, and alpha-1-antitrypsin deficiency diseases. There is also a chapter on non-infectious pulmonary manifestations after organ and bone marrow transplantation (not including heart–lung or lung transplantation) and on acute respiratory distress syndrome (ARDS). The editors very much hope that this European Respiratory Monograph will provide the reader with an interesting overview and update on the possible pulmonary involvement and specific treatment options in different systemic diseases.

  • European Respiratory Society Monographs
  1. Page viii
  2. Page 1
    Correspondence: R. Westhovens, Dept of Rheumatology, UZ Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium. Fax: 32 16342543; E-mail:

    Connective tissue disorders, such as rheumatoid arthritis, systemic lupus erythematosus, Sjögren’s syndrome, systemic sclerosis and the idiopathic inflammatory myopathies, are relatively rare diseases, although their high morbidity and, sometimes, increased mortality, especially due to the pulmonary involvement, pose important challenges to the treating physicians.

    As their aetiopathogenesis is still incompletely understood, disease classification systems have given us more insight into the differential clinical organ involvements and prognosis; the most important example of this is difference between diffuse systemic sclerosis with rapidly deteriorating interstitial lung disease, and limited systemic sclerosis, sometimes with late pulmonary hypertension.

    Disease activity indices are, in these diseases, with the exception of rheumatoid arthritis, less well validated, making clinical therapy trials difficult. However, a disease activity index such as the British Isles Lupus Assessment Group also evaluates different organ systems separately and has shown promising results in clinical trials of systemic lupus.

    Better understanding of the aetiopathogenetic features will undoubtedly lead to better therapeutic strategies for patients. Some of the typical autoantibodies (although with different sensitivity and specificity for the distinct systemic diseases) might also play an aetiopathogenetic role, an important finding when anti-B-cell therapies become available. Understanding the basic immunological mechanisms and the cytokine network, especially in lung pathology, may lead to more specific biological therapies.

    Lung fibrosis, which is one of the hallmarks of those diseases, is becoming better understood and this will hopefully lead to additional therapies to the current anti-inflammatory strategies. Also, insights into the role of the pulmonary vascular system and genetic associations will increasingly alter the current view on these challenging disorders. Undoubtedly, a multidisciplinary approach in registrating/validating disease activity and damage indices, performing clinical trials and enhancing the understanding of the basic mechanisms behind them will lead to major benefits for the patients.

  3. Page 27
    Correspondence: J.C. Grutters, Heart Lung Center Utrecht, Dept of Pulmonology, St. Antonius Hospital, Koekoekslaan 1, 3435 CM Nieuwegein, The Netherlands. Fax: 31 306052001; E-mail:

    Interstitial lung involvement is a key complication of connective tissue disorders (CTD). Most histopathological–radiological entities seen in idiopathic interstitial pneumonias (IPs) can be found, i.e. nonspecific IP, usual IP, organising pneumonia, lymphocytic IP and diffuse alveolar damage. However, making a distinction between these entities in CTD seems to have less importance in terms of prognosis and response to therapy, not justifying routine lung biopsy for a diagnosis. At present lung function testing and high-resolution computed tomography of the chest are central to the initial assessment of interstitial lung disease in CTD. In addition, measurement of serum pneumoproteins like Krebs von den Lungen (KL)-6, a glycoprotein expressed on type II pneumocytes, appears a promising new tool, especially for detection. However, more studies are required to evaluate the usefulness in the follow-up of fibrosing IPs. Bronchoalveolar lavage is advocated for its role in excluding other causes of parenchymal involvement in CTD, e.g. infections, drug reactions and capillaritis with diffuse alveolar haemorrhage.

    Corticosteroids and immunosuppressive drugs like cyclophosphamide, azathioprine and methotrexate are still the mainstay of therapy for symptomatic/progressive IPs in CTD, although there is hardly any evidence from randomised, controlled trials. For systemic sclerosis (SSc)-associated IPs, there are presently two important studies underway investigating cyclophosphamide as a treatment, from which outcome data should become available in 2005 (the Scleroderma Trial (FAST) in Europe; the Scleroderma Lung Study (SLS) trail in the USA). Tumour necrosis factor-α blocking molecules are widely used for the treatment of rheumatoid arthritis, but their effectiveness and safety in patients with lung involvement needs further study. In addition, new insights in the underlying fibrotic processes of IPs have provided promising antifibrotic drug strategies that are now under evaluation, e.g. transforming growth factor-β1 antibodies and endothelin antagonists. Finally, in patients with systemic disease and end-stage pulmonary fibrosis, especially SSc, lung transplantation should be considered in those without active disease and preserved function in other organs. In such a case, results after transplantation are similar to other disease conditions.

  4. Page 50
    Correspondence: M. Thomeer, Dienst Longziekten, Ziekenhuis Oost Limburg, Schiepse Bos 6, 3600 Genk, Belgium. Fax: 32 16346803; E-mail:

    Since the Chapel Hill Consensus Conference on the Nomenclature of Systemic Vasculitis, substantial developments in the understanding of the pathogenesis of different forms of vasculitides have been made. Animal models have been developed, with possible important implications as to how patients with vasculitis will be treated in the future. The different mechanisms of endothelial injury have been elucidated further. This article reviews the clinical spectrum of vasculitis and how research has helped in the understanding of the pathogenesis of the different forms vasculitis.

  5. Page 69
    Correspondence: M. Thomeer, Dienst Longziekten, Ziekenhuis Oost-Limburg, Schiepse Bos 6, 3600 Genk, Belgium. Fax: 32 16346803; E-mail:

    Pulmonary vascular inflammation may be seen in a variety of primary lung diseases and in the setting of numerous systemic illnesses. The present article reviews those entities in which pulmonary vasculitis represents a central feature of the pathological process. The different clinical manifestations, use of autoantibodies and approach to diagnosis are discussed. In addition, general principles for the treatment of vasculitis in different clinical settings, but also possible new treatment modalities, are reviewed.

  6. Page 91
    Correspondence: E.K. Verbeken, Dept of Pathology, University Hospital Gasthuisberg, 49 Herestraat, B-3000 Leuven, Belgium. Fax: 32 16336548; E-mail:

    The diagnosis of a small-vessel vasculitis syndrome is usually not straightforward.

    Small-vessel vasculitis is an inflammatory destructive process affecting small arteries, arterioles, capillaries and venules. These syndromes have some general principles in common with regard to pathogenesis (immune complexes versus anti-neutrophil cytoplasmic antibody-associated), anatomical distribution (limited versus extensive disease) and clinicopathological presentations, also in the setting of connective tissue diseases. This is presented in the section on “General principles”. A second section deals with specific small-vessel vasculitis syndromes affecting the lung and how they fit into the general principles of the latter syndromes.

  7. Page 102
    Correspondence: W. De Backer, Dept of Pulmonary Medicine, University of Antwerp, Wilrijkstraat 10, 2650 Edegem-Antwerp, Belgium. Fax: 32 38214447; E-mail:

    Patients with renal failure may develop pulmonary oedema due to fluid overload, hypoproteinaemia with reduced plasma colloid pressure and depressed myocardial function. Pleural effusions can also occur. Transudative pleural effusions are caused by hypervolaemia or congestive heart failure. Exudative pleural effusions can be caused by uraemia as a result of pleural inflammation. Renal failure appears to be associated with an increased risk of respiratory tract infections. The increased prevalence of tuberculosis is particularly well established. Haemodialysis may induce changes in lung function and gas exchange. Hypoxaemia during haemodialysis, and more generally during extracorporeal circulation, is due to trapping of neutrophils in the pulmonary circulation (and subsequent release of inflammatory mediators and oxygen radicals) and to alveolar hypoventilation (due to venous carbon dioxide unloading).

  8. Page 112
    Correspondence: P. Schenk, Dept of Internal Medicine IV, Medical University Vienna, Allgemeines Krankenhaus, Waehringer Guertel 18–20, A-1090 Vienna, Austria. Fax: 43 1404004797; E-mail:

    Hepatopulmonary syndrome (HPS) complicates several liver diseases and is characterised by the typical triad of liver disease (usually cirrhosis), intrapulmonary vasodilation at the capillary and pre-capillary level, and pathological arterial oxygenation. It may coexist with primary cardiopulmonary diseases. Mostly, diffuse intrapulmonary vasodilation near the gas exchange area is present (with consecutive, impaired haemoglobin oxygenation in the central capillary blood flow); rarely, localised arteriovenous anastomoses can be detected. Functional changes are impaired ventilation/perfusion mismatch, increased right-to-left shunt and diffusion impairment. The sole typically abnormal lung function parameter is reduced diffusion capacity of the lung for carbon monoxide. Increased production of nitric oxide is considered as the main mediator for vasodilation. Diagnosis is based on arterial blood gas analysis (reduced arterial oxygen tension or elevated alveolar–arterial oxygen tension difference) and a positive contrast echocardiography or 99mtechnetium-macroaggregated albumin scan. Reported prevalence in patients with cirrhosis is 5–32%, and mortality is high (HPS is an independent risk factor). The only established therapy is liver transplantation.

  9. Page 129
    Correspondence: M. Delcroix, Dept of Respiratory Diseases, University Hospital Gasthuisberg, 49 Herestraat, B-3000 Leuven, Belgium. Fax: 32 16346803; E-mail:

    Liver disease may affect the lungs. A small proportion of patients, ∼1%, develop pulmonary hypertension, which is known as portopulmonary hypertension (PoPH) and is classified under the heading pulmonary arterial hypertension. It is clinically indistinguishable from idiopathic pulmonary arterial hypertension, and responds similarly to prostacyclin therapy. Unlike the hepatopulmonary syndrome, PoPH is irreversible and, in the moderate-to-severe stages, liver transplantation is not widely recommended, and is even regarded as a contraindication due to its negative peri- and post-operative impact. As a consequence, screening by repeated transthoracic echocardiography is highly recommended in liver transplant candidates. Therapy with prostacyclin analogues may partially relieve this pulmonary hypertension. The safety and efficacy of oral endothelin receptor antagonists and oral phosphodiesterase inhibitors is currently under evaluation. Transjugular intrahepatic portosystemic shunt may worsen pulmonary haemodynamics.

  10. Page 139
    Correspondence: J. Stolk, Dept of Pulmonology, C3-P, Leiden University Medical Center, Albinusdreef 2, P.O. Box 9600, NL-2300 RC Leiden, The Netherlands. Fax: 31 715266927; E-mail:

    Alpha-1-antitrypsin deficiency (AATD) is classically associated with the early onset of severe basal emphysema, but is also associated with the development of cirrhosis, primary carcinoma of the liver and possibly the vasculitides. All these decrease life expectancy, although the pulmonary condition dominates, as emphasised by the additive effect of cigarette smoking on mortality in patients with deficiency. In those aged over 50 yrs, a proportion of the deficient subjects may develop increasing airflow obstruction which was shown to be related to a history of wheezing and occupational exposure to irritants. This raises the possibility that asthma may be a predisposing factor to the development of permanent airflow obstruction in nonsmokers with AATD and supports one of the World Health Organization’s recommendations that all adults with asthma should be tested for this deficiency. Central to the pathology of AATD is the accumulation of aberrant forms of misfolded or polymerised α1-antitrypsin rather than a failure to produce the protein, and strategies to develop small peptides that can selectively inhibit polymerisation of the Z allele of the α1-antitrypsin protein in the liver is the common theme to repair this conformational disease.

  11. Page 151
    Correspondence: B. Wallaert, Service de Pneumologie et Immuno-Allergologie, Hôpital Calmette, bd du Professeur Leclercq, CHRU Lille, 59037 Lille cedex, France. Fax: 33 320445768; E-mail:

    Bronchopulmonary involvement is quite uncommon in Crohn’s disease (CD). It may concern either patent or latent manifestations. Patent manifestations include specific lung disorders related to CD, overlapping syndromes (sarcoidosis, Wegener’s granulomatosis and amyloidosis), iatrogenic complications concerning drug-induced diseases, and opportunistic infections, as well as thromboembolism. Latent manifestations encompass pulmonary functional testing alterations, bronchoalveolar fluid cells abnormalities and computed tomographic scan changes in asymptomatic patients. The aetiology of lung injury may be difficult to determine and requires extensive exploration, including histological data.

  12. Page 168
    Correspondence: Ph. Camus, Division of Pulmonary Medicine and Intensive Care, CHU Le Bocage and Université de Bourgogne, Box 1542, F-21034 Dijon, France. Fax: 33 380293625; E-mail:;

    To some extent, the respiratory manifestations of ulcerative colitis (UC) overlap with those of Crohn’s disease. These manifestations can develop at any time with respect to the clinical onset of the UC. They can also predate the UC, or develop after colectomy. These manifestations must be differentiated from adverse reactions to drugs used to treat the inflammatory bowel disease. The respiratory manifestations of UC (and typical or possible presentations) include inflammatory involvement of the trachea (cough, stridor, asphyxia), large airways (cough, sputum, haemoptysis), bronchial suppuration and bronchiectasis (cough, sputum), small airway inflammation (bronchiolitis, chronic airflow obstruction), variegated forms of infiltrative lung disease (fever, dyspnoea, respiratory failure), necrotic nodules (fever, cavitating lung nodules) and serositis (chest pain, tamponade). Many cases of airway involvement respond to inhaled steroids, or to a combination inhaled and systemic steroids. Early recognition and treatment are encouraged to minimise irreversible airway damage.

  13. Page 184
    Correspondence: J.A. Kastelik, Division of Academic Medicine, Castle Hill Hospital, Castle Road, Cottingham, East Yorkshire HU16 5JQ, UK. Fax: 44 1482624068; E-mail.

    Respiratory and gastrointestinal tracts have similar embryological origins. Therefore, some respiratory conditions may be related to disorders of the gut. Microaspiration and vagally mediated reflex are the most commonly discussed pathological explanations for this association. There is now increasing evidence that gastro-oesophageal reflux can be related to chronic cough. Similarly, gut disorders may contribute to respiratory conditions, such as asthma, interstitial lung diseases, bronchiectasis or chronic respiratory pulmonary disease. Epidemiological studies suggest increased prevalence of respiratory conditions in subjects with gut disorders. Similarly, gut disorders are frequently observed in patients with respiratory diseases. Whether these observations represent true association between conditions of the gut and the lungs remains unknown. Similarly, debate continues whether anti-reflux therapy is beneficial in respiratory conditions. The present review discusses these issues.

  14. Page 202
    Correspondence: L.J. Dupont, Respiratory Medicine, University Hospital Gasthuisberg, 49 Herestraat, B-3000 Leuven, Belgium. Fax: 32 16346803; E-mail:

    Respiratory complications are important contributors to post-operative morbidity and mortality after organ transplantation. New insights about the noninfectious pulmonary complications are the subject of the present review.

    Pulmonary complications after kidney transplantation are reported to occur in 5–24%. Infectious complications, such as pneumonia, account for more than half of these pulmonary complications. Noninfectious complications following renal transplant include atelectasis, pulmonary oedema, thrombo-embolic disease and post-transplant malignancies.

    Pulmonary complications after orthoptic liver transplantation are more frequent, with a prevalence ranging between 60 and 87%. The majority of these pulmonary complications following liver transplantation are noninfectious in origin. The immediate post-operative noninfectious complications, such as atelectasis, pneumothorax, pleural effusion and pulmonary oedema, are usually self-resolving. Other noninfectious complications after liver transplantation include ARDS, pulmonary haemorrhage and right diaphragm dysfunction, pulmonary calcifications, pulmonary fibrosis, bronchiolitis obliterans organising pneumonia and neoplastic disease.

    Pulmonary complications following orthoptic heart transplantation may develop in up to one-third of cardiac transplant recipients, although most common pulmonary complications consist of pneumonia and bronchitis. Noninfectious complications involve pneumothorax and pleural effusion, thromboembolic disease, obstructive sleep apnoea syndrome, pulmonary malignancy, pulmonary interstitial fibrosis, exercise-induced hypoxaemia and diffusion abnormalities.

    With the use of prophylactic antibiotics, the spectrum of pulmonary complications following stem cell transplantation has changed increasingly from infectious to noninfectious aetiologies. Early phase noninfectious pulmonary complications include pulmonary oedema, diffuse alveolar haemorrhage and idiopathic pneumonia syndrome. Late phase noninfectious pulmonary problems include complications that are due to chronic graft-versus-host disease and associated bronchiolitis obliterans, and also include restrictive lung disease.

    A direct negative effect on the lungs of some immunosuppressive drugs, such as cyclosporine, sirolimus and azathioprine, has been suggested but only very few cases were reported.

  15. Page 220
    Correspondence: A.D.B. Webster, Primary Immunodeficiency Clinic, Clinical Immunology, 2nd Floor, Royal Free and University College Medical School, Pond Street, London NW3 2PF, UK. Fax: 44 2078302224; E-mail:

    Clinical observations in patients with primary antibody deficiency (PAD) have shown that antibodies play an important role in protecting the respiratory system from infection, particularly caused by bacteria such as Haemophilus influenzae and pneumococci. The treatment of this complication is still unsatisfactory, with >50% of patients suffering from recurrent or persistent bronchitis despite immunoglobulin (Ig) replacement therapy and various antibiotic regimes.

    PAD patients are prone to mycoplasma infections, but Mycoplasma pneumoniae is the only type known to unequivocally infect the lung. A novel strain (M. amphoriforme) has recently been found in the sputum of many PAD patients with chronic bronchitis, but it is not known if this organism is a true pathogen. The role of viruses in the lung pathology of PAD patients is not clear, but there is some evidence that respiratory viruses may persist in the lungs for prolonged periods.

    There is no consensus on the best use of antibiotics in PAD patients, with a need for long-term multicentre studies comparing different prophylactic regimes. There is also no consensus on the optimal dose and route of administration of replacement Ig, although most clinics aim for a serum IgG level above the lower limit of the normal range.

    Patients with common variable immunodeficiency may develop granulomatous infiltration of the lung, the clinical and radiological features having similarities with sarcoidosis. The cause is not known but this complication usually responds to steroids, although most affected patients have to be maintained on ∼10 mg·day−1 long term. Other anti-inflammatory strategies, such as infliximab therapy, need to be explored.

  16. Page 234
    Correspondence: E.F.M. Wouters, Dept of Respiratory Medicine, University Hospital Maastricht, P.O. Box 5800, 6202 AZ Maastricht, The Netherlands. Fax: 31 433875051; E-mail:

    This article provides a review of how endocrine and metabolic disorders affect the respiratory system. Emphasis is placed on the pulmonary manifestations of thyroid disorders, diabetes mellitus and respiratory complications related to obesitas and nutritional depletion.

  17. Page 253
    Correspondence: J-L. Vincent, Dept of Intensive care, University Hospital Erasme, Free University of Brussels, Route de Lennik 808, 1070 Brussels, Belgium. Fax: 32 25554555; E-mail:

    Acute respiratory distress syndrome (ARDS) is characterised by the association of severe hypoxaemia, bilateral infiltrates on chest radiograph, and the absence of any evidence of increased hydrostatic pressure. Sepsis and ARDS are common partners, with sepsis being the most frequent risk factor for ARDS, and the presence of sepsis in a patient with ARDS is associated with increased mortality rates. The two conditions share the same complex mediator-mediated process involving different cellular components and an important inter-relation between inflammation and coagulation.

    Alterations in capillary permeability, under the influence of these mediators, results in “nonhaemodynamic” pulmonary oedema, an increase in extravascular lung water that is not primarily due to an increase in hydrostatic pressures. There are also alterations in surfactant and, in more severe cases, fibrosis occurs. Although the process appears quite diffuse on the chest radiograph, the use of computed tomography has shown that the process is not so homogenous: there are dependent zones which have collapsed, zones that are “recruitable” and zones that are well ventilated.

    Mortality rates from ARDS are still very high at 30–50%, with outcome usually better in trauma than in sepsis and in surgical patients than in medical patients. When death occurs, it is due to multiple organ failure in 80% of cases, reflecting the systemic nature of the disease, and to refractory hypoxia in barely 20%. Thus, systemic management is of paramount importance and must primarily focus on treatment of the underlying cause, e.g. the infection causing the sepsis.

    Other treatments are primarily supportive and include avoidance of fluid overload while ensuring sufficient fluid administration to maintain oxygen delivery (and thus sufficient blood flow) to the tissues. High tidal volumes should be avoided, as shown by the ARDS Network study. If the ARDS is sepsis related, activated protein C should be given if the patient meets the criteria for this drug.

  18. Page 262
    Correspondence: B.M-A. Buyse, Dept of Pulmonology, Centre for Sleep Monitoring and Home Ventilation, University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium. Fax: 32 16346803; E-mail:

    The key points covered in this chapter are as follows. 1) Symptoms of respiratory failure in central neural, neuromuscular and osteo-articular chest wall disorders are often insidious, particularly when the inability to ambulate occurs in tandem with respiratory weakness. Respiratory muscle weakness primarily contributes to sleep-disordered breathing, consequently, sleep-related complaints, such as poor sleep, daytime somnolence, and morning headache, are common. 2) Respiratory failure in central neural, neuromuscular and osteo-articular chest wall disorders is primarily due to ventilatory failure. Consequently, home ventilation is the treatment of choice, not long-term oxygen administration. 3) Weakness of the expiratory muscles has less impact on ventilatory function. However, expiratory muscles are essential to the generation of an effective cough. Their function should be monitored and also assisted. 4) The adverse effects of the inability to clear secretions are amplified if the patient also demonstrates weakness of the upper airway musculature, which is often present in the case of neuromuscular diseases and the source of often lethal aspiration pneumonia. 5) In several neuromuscular diseases, decreased chest wall compliance, either primarily in the case of osteo-articular diseases or secondary to neuromuscular diseases due to stiffening of tendons and ligaments of the ribcage and kyphoscoliosis, as well as decreased lung compliance, contributes to increased work of breathing. 6) Chest wall diseases, nervous system diseases, neuromuscular diseases, respiratory function, respiratory insufficiency and respiratory muscles are discussed.

  19. Page 290
    Correspondence: L.M. Delaunois, Dept of Respiratory Diseases, Catholic University of Louvain, University Clinics of Mont-Godinne, Avenue Therasse 1, B-5530 Yvoir, Belgium. Fax: 32 81423352; E-mail:

    As the lungs, the great vessels and the heart share the main volume of the thorax, itself limited by the thoracic wall, the variation in pressure or volume of each one must influence the working of the others, especially in the case of disease. Failure of the left side of the heart overloads the pulmonary vascular bed, and induces an interstitial oedema followed by an alveolar oedema with mostly restrictive functional consequences on the lung and disturbed gas exchange. These consequences of myocardial and valve diseases of the left side of the heart are initially revealed by unusual dyspnoea during exercise that worsens progressively to symptoms at rest and even during sleep.

    Information obtained from history, physical examination, radiography and echocardiography imaging procedures, respiratory function tests and polysomnography help to determine the diagnosis and prognosis. Conversely, many respiratory diseases can induce pulmonary artery hypertension, followed by overload and failure of the right side of the heart, which can affect the survival. Moreover, this right-sided heart failure can modify the geometry of the cardiac interventricular septum and hasten left-sided heart failure.

    Finally, due to its intrathoracic situation, the heart is submitted to the variations of pleural pressure that can positively influence its post-load or negatively influence its pre-load with consequences on its work.