Pulmonary Manifestations of Systemic Diseases (out of print)

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.

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.

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.

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.

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.

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.

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.

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.

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.