Airway bypass aims to improve respiratory mechanics by creating new exit pathways for air t rapped in emphysematous lungs. The wall of a segmental bronchus is punctured under bronchos copic guidance and a stent is inserted, creating an internal bronchopulmonary communication for expi- ration. Hence, hyperin \202 ation decreases and lung mechanics are improved. Th is is at an early stage of research. Further information Naunheim KS et al. Long term follow-up of patients receiving LVRS vs. m edical therapy for severe emphysema by the NETT research group. Ann Thoracic Surg 2006; 82: 431 \200\22343 Fishman A et al. A randomized trial comparing lung-volume-reduction surgery with medical th erapy for severe emphysema. N Engl J Med 2003; 22: 2059 \200\22373. Criner GJ et al. Prospective randomized trial comparing bilateral LVRS to pulmonary rehabil itation in severe COPD. Am Resp Crit Care Med 1999; 160: 2018 \200\22327 Geddes D et al. Effect of LVRS in patients with severe emphysema. NEJM 2000; 343: 239 \200 \22345 Toma TP et al. Bronchoscopic volume reduction with valve implants in patients with severe e mphysema. Lancet 2003; 361: 931 \200\2233 Benditt JO. Surgical therapies for COPD. Respir Care 2004; 49: 53 \200\22363 182 CHAPTER 21 Chronic obstructive pulmonary disease a1-antitrypsin (a1-AT) de \201 ciency This is an inherited condition that is associated wi th the early development of emphysema. It is common (estimated 1 in 2000 \200\2235000 indiv iduals) and is probably under-diagnosed, as it is often asymptomatic in non-smokers. Pathop hysiology A1-AT is a glycoprotein protease inhibitor produced by the liver. It is secreted via the bloodstream into the lungs and opposes neutrophil elastase, which destroys alveolar wall connective tissue. Elastase is produced in increased levels by pulmonary neutrophils and macro- phages in response to smoking and lung infections. If A1-AT is de \201 cient, t he elastase cannot be opposed, and subsequently basal emphysema develops. The disease is wo rse in smokers and can cause COPD at a young age (40s and 50s). There may also be associate d liver dysfunction, chronic hep- atitis, cirrhosis, and hepatoma, as abnormal protein secr etion accumulates in the liver. Predisposition also to skin disease (panniculitis) and vasc ulitis (especially ANCA +). Genetics A1-AT de \201 ciency is inherited as an autosomal co- dominant dis- order. So far more than 100 different alleles have been identi \201 ed for t his gene (SERPINA 1) on the long arm of chromosome 14. The commonest alleles are the M alle le (normal), the partially defective S allele, and the almost fully defective Z allele (lys ine is substituted for glutamic acid at position 342, leading to abnormal folding, preventi ng post-translational processing with retention within cells), commonest in Scandinavia. \200 \200 MM, the normal phenotype. Background population risk of emphysema MS, MZ have 50 \200\22370 % of normal A1-protease inhibitor (Pi) levels. Back- ground risk of emphysema SZ, SS have 3 5 \200\22350% of normal levels. 20 \200\22350% risk of emphysema Homozygous ZZ has only 10 \200\22320% of normal levels. 80 \200\223100% risk of emphysema \200 Screening for the defect should be carried out especially in patients <40 with COPD. Also p atients with unexplained liver disease should be screened. Send blood for A1-AT concentrati ons and genotyping if levels are low. Siblings should be screened and the particular import ance of not smoking and avoiding passive smoking emphasized. Non-smokers are usually asympt omatic. Treatment includes usual therapy for COPD. Speci \201 c treatment is known as augm entation therapy, with weekly/2-weekly/monthly infusions of puri \201 ed A1-AT from pooled human plasma. This raises concentrations in serum and epithelial-lining \202 uid above t he protective threshold. It appears to be safe, with minimal side-effects. A large cohort s tudy showed reduced mortality amongst infusion recipients, with a slowing of lung function decline (by 27 ml/year, p = 0.03) in a subgroup with moderate emphysema. An RCT showed no s igni \201 cant differences between augmentation and control groups, although there was a t rend towards slower loss of lung tissue on CT scan in the augmentation group (p = 0.07). It has, however, been recommended as a treatment by groups including the ATS and ERS A1-ANTITRYPSIN DEFICIENCY 183 for those with moderate (FEV1 35 \200\22360% predicted) emphysema due to A1-AT de \201 cie ncy, but not those with mild or severe disease or those post lung transplant for A1-AT de \201 ciency, except during episodes of acute rejection and infection (when in \202 ammatio n causes free elastase activity). It is expensive and its cost-effectiveness in terms of co st per year of life saved is high. It is, however, the only speci \201 c therapy available at present. Future developments Inhaled A1-AT may provide a way of delivering the enzyme t o the lower respiratory tract to have its action locally and potentially reduce in \202 am mation. Gene therapy is under development, \201 nding ways of delivering the A1-AT gene i nto the cell. Other strategies include inhi- bition of hepatic polymerization of A1-AT, pro motion of hepatic secretion, inhibition of neutrophil elastase by synthetic inhibitors to a void the use of human plasma, and pegylation of A1-AT to prolong its serum half-life. Further information ADAPT program (Antitrypsin de \201 ciency Assessment and Program for T reatment) www. aatregistry.org/ukusa.html headed by Prof R Stockley, Queen Elizabeth Hospit al Birmingham. Aims to have a comprehensive database of all patients with 1-antitrypsin d e \201 ciency in the UK, as well as offering assessment and treatment in a single UK cente r. Stoller JK, Aboussouan LS. 1-antitrypsin de \201 ciency. Lancet 2005; 365: 2225 \200\223 36 Review series: 1-antitrypsin de \201 ciency. Thorax 2004: 59: 64 \200\2239, 259 \200\223 64, 441 \200\2235,529 \200\22335, 708 \200\22312, 904 \200\2239 UK alpha1 antitrypsin de \201 ciency support group www.alpha1.org.uk/index.html This page intentionally left blank 185 Chapter 22 Connective tissue disease and the lung Differential diagnosis and standard tests 186 Rheumatoid arthritis (RA) 188 Systemic lupus erythematosus (SLE) 190 Polymyositis and dermatomyositis 192 Systemic sclerosis 194 Sj gre n \200\231s syndrome 196 Ankylosing spondylitis 197 Beh et \200\231s syndrome 198 186 CHAPTER 22 Connective tissue disease and the lung Differential diagnosis and standard tests Patients with connective tissue diseases can deve lop pulmonary compli- cations, for which they might be referred to a chest physician. Patie nts typically present with symptoms of dyspnoea, cough, fever, or chest pain. They may ofte n be on immunosuppressive drugs. Differential diagnosis In practice, the main differential diagnosis lies between: Opportunistic pulmonary infection \200 May be in those on immunosuppressive drugs, or functionally immuno- suppressed from underly ing disease Any usual organism, also TB, non-tuberculous mycobacteria, PCP, fungi, cytomega lovirus Often acute onset with non-speci \201 c features of low-grade fever, productive co ugh, raised in \202 ammatory markers Can be very unwell and need full supportive treatment with ITU. Original connective tissue disease now affecting the lung \200 \200 Often in \202 ammation or \201 brosis Usually more indolent presentation, with dry cough and dyspnoea, but can become acutely unwell with background of chronic lung disease Fine i nspiratory crackles on auscultation Consider development of pulmonary hypertension in patie nts with systemic sclerosis. \200 New pulmonary pathology \200 Unrelated to the original condition, including pulmonary thromboembolic disease. Drug side-effects \200 Methotrexate \200\224pneumonitis occurs in 5% of patients receiving methotrexate. Potential ly life-threatening. Mortality 15 \200\22320%. Cough, fever, dyspnoea, widespread crackles, restrictive defect, and pulmonary in \201 ltrates on CXR and CT. Peripheral eosinophilia in 50%. BAL lymphocytosis. Usually subacute onset, but may be sudden. Usually within 4 mont hs of starting methotrexate. Non-speci \201 c histological \201 ndings. No more common i n those with pre-existing lung disease. Treatment: stop the drug, commence steroids, and av oid methotrexate in the future. Can be reversible. Can get mild intractable cough with meth otrexate Gold \200\224alveolar opacities seen on HRCT, with associated fever and skin rash. BAL lymphocytosis. Treatment: stop the drug and commence steroids. Usually reversible Peni cillamine \200\224causes obliterative bronchiolitis in rheumatoid arthritis. Can also cause a hypersensitivity pneumonitis and a pulmonary \200\223renal syndrome causing alveolar hem orrhage. May respond to stopping the drug. DIFFERENTIAL DIAGNOSIS AND STANDARD TESTS 187 Standard tests to consider for the investigation of these patients \200 \200 \200 \200 \200 \200 \200 Oxygen saturations and blood gas CXR HRCT Culture of respiratory secretions Pulmonary fu nction tests, including KCO Autoantibody and in \202 ammatory marker levels Bronchoscopy a nd bronchoalveolar lavage Transbronchial or open lung biopsies. For an approach to: \200 \200 Diffuse lung disease, see p 29 Diffuse alveolar hemorrhage, see p 25 Pulmonary disease in t he immunocompromised host (non-HIV), see p 67. 188 CHAPTER 22 Connective tissue disease and the lung Rheumatoid arthritis (RA) \200 \200 Persistent deforming symmetrical peripheral arthropathy Pulmonary disease is commoner in me n and occasionally occurs before the development of joint problems Pneumonia is a common te rminal event, causing 15 \200\22320% of rheumatoid arthritis deaths Pleuritis Frequent, occurring in more than 30% of patients and usually mild. Pleuritic pain , with no obvious other cause. Pleural effusion Usually asymptomatic. Fluid is typically ex udative with a low glucose and low pH and usually a lymphocytosis. Need to exclude other ca uses for effusion, such as empyema or malignancy. If problematic, may require drainage and steroids. (See p 360.) Pulmonary \201 brosis Minor pulmonary \201 brosis found in up to 60% of patients in lung biopsy studies, but CXR changes only seen in 1 \200\2235%. Hence s ymptomatic disease is unusual. Tends to occur in patients who have multi- system disease, i ncluding vasculitis, and those with nodules, seropositive disease, and high ANA titres. Mor e common in men, and smoking is a risk factor for \201 brosis development. \200 \200 \200 \200 Presents with progressive dyspnoea Examination: clubbing and bilateral basal crepitations P FTs: low kCO, restrictive pattern Radiologically and histologically similar to usual inters titial pneumonitis (UIP), with subpleural basal reticular pattern, but can be like non- spe ci \201 c interstitial pneumonitis (NSIP) Treatment: steroids or immunosuppressants do lit tle to change the course, but should be tried Acute pneumonitis also recognized, which presents with rapidly deterio- rating dyspnoea and development of respiratory failure, or acute deterio- ration on a background of chronic \201 brosis. Acute pneumonitis tends to be more steroid responsive. Pulmonary nodules occur in less than 5% of patients with RA. Usually found incidentally on CXR. Only occur in sero positive disease, and patients may have other nodules elsewhere, such as elbows and \201 ngers. Single or multiple; may measure up to 7 cm. May cavitate and cause haemoptysis or pn eumothorax. Mostly asymptomatic. Main differential diagnosis is lung cancer. Usually follow ed on CT to ensure they are of stable size. They typi- cally show mild uptake on PET, consi stent with other benign lesions. May need biopsy to exclude malignancy. Bronchiectasis is o ften subtle with minimal clinical features, but may be found in 30%. May be seen in associa tion with pulmonary \201 brosis. Diagnosis made on HRCT. Organizing pneumonia The clinica l syndrome of pneumonia with fever, dyspnoea, and multifocal consolidation, which do not re spond to antibiotics. Can be disease- or drug-induced (gold), or have no obvious cause, and is then known as cryptogenic (see p 270). Con \201 rmed by trans- bronchial or open lung biopsy showing acini \201 lled with loose connective RHEUMATOID ARTHRITIS 189 tissue and a variable in \202 ammatory in \201 ltrate. Often a dramatic response to stero ids. May need long-term immunosuppression. Obliterative bronchiolitis Rare. Terminal bronch ioles progressively obliterated by in \202 ammatory connective tissue. \200 May present with dyspnoea and hyperin \202 ated chest, with basal crepita- tions PFTs: irr eversible obstructive pattern CXR: hyperin \202 ation, no in \201 ltrates HRCT: mosaic pa ttern Biopsy shows destruction of terminal bronchiolar wall by granulation tissue, effaceme nt of the lumen, and replacement of the bronchiole by \201 brous tissue. Irreversible pat hology, usually unresponsive to treatment May be rapidly progressive Can give trial of oral steroids, continuing with high-dose inhaled ster- oids if any response. Consider transplan t. Penicillamine was thought to be a causative factor, but the evidence for this is now wea ker. \200 \200 \200 \200 Vasculitis and rarely pulmonary hemorrhage. Cricoarytenoid arthritis Seen in studies in up to 75% of patients with rheumatoid arthritis by \201 bre-optic laryngoscopy and HRCT, but rarely symptomatic. Unrelated to lung \201 brosis. Can cause sore throat, hoarse voice, upper airways obstruction with stridor, or OSA. Flow \200\223volume loop may be abnormal. T his may need tracheostomy and steroids \200\224oral and joint injection. Caplan \200\231s s yndrome Rheumatoid arthritis, single or multiple chest nodules, and coal-worker s pneumocon iosis. 190 CHAPTER 22 Connective tissue disease and the lung Systemic lupus erythematosus (SLE) \200 \200 Multi-organ autoimmune disease, mainly affecting women Double-stranded DNA antibodies prese nt in high titres and these may be the causative agent Can also get a drug-induced lupus sy ndrome, which improves when the drug is stopped Pulmonary disease often seen and may be a p resenting feature of the disease Pleural disease Most common manifestation of pulmonary disease. Often asymptomatic, but may have pain due to pleuritis. Pleural effusions found in 50% of patients, which cause breath lessness. These are often bilat- eral and exudative, with a neutrophilia or a lymphocytosis if the effusion is chronic. Can be haemorrhagic. Pleural biopsy \201 ndings are non-spec i \201 c. Need to exclude other causes for effusion, such as empyema or malignancy. If sym ptomatic, may need treatment with non-steroidal anti-in \202 ammatory drugs or steroids. A telectasis associated with pleurisy or effusion. Diffuse lung disease Occurs in up to 70% o f patients, but usually mild and asymptomatic. Radiologically similar to rheumatoid lung \201 brosis. Only 5% develop clinical disease similar to UIP with dyspnoea, cough, and basa l crackles. May be associated with pleuritic pain. PFTs show restrictive defect with reduce d kCO. Rarely, progressive and severe. Acute lupus pneumonitis In <2%, severe illness with high mor- tality rate of over 50%. Cough, dyspnoea, fever, pleuritic pain, hypoxia. Widespr ead crackles. CXR shows in \201 ltrates, which may be widespread. Histologically non-speci \201 c. Need to exclude infection, pulmonary oedema. Treatment with steroids and cytotoxi c drugs may be necessary and may have dramatic response. Can progress to chronic interstiti al pneumonitis. Bronchiolitis obliterans See p 161. Pulmonary nodules See p 312. Pulmonary hypertension due to pulmonary vasoconstriction, rather than pulmonary vasculitis. Commoner in those with Raynaud \200\231s phenom- enon. Associated with poorer prognosis: 50% 2-year mortality. Diagnosed on echocardiography. Need to exclude pulmonary emboli as a cause, espe cially in those with antiphospholipid antibodies. Treatment as for idi- opathic pulmonary h ypertension (see p 394). Pulmonary emboli Commoner in the 20 \200\22330% with antiphospholi pid antibodies. Shrinking lung syndrome Dyspnoea caused by reduced lung volumes and poor re spiratory reserve due to diaphragmatic muscle weakness. Small lungs on CXR. Normal lung par enchyma on CT. Restrictive lung function tests, with high kCO. May improve with steroids. A lveolar hemorrhage Rare. May be life-threatening. Can have asso- ciated glomerulonephritis. Acute dyspnoea with in \201 ltrates on CXR. Raised kCO. Treat with high-dose steroids + c yclophosphamide. SYSTEMIC LUPUS ERYTHEMATOSUS 191 Criteria of the American College of Rheumatology for the classi \201 cation of SLE SLE if 4 or more criteria present, serially or simultaneously, during any interval \200 \200 \200 \200 \200 \200 \200 \200 Malar rash Discoid rash Photosensitivity Oral ulcers Arthritis Serositis Pleuritis or peric arditis Renal disorder: proteinuria >0.5 g/24 h or 3+ persistently, or cellular casts Neuro logical disorder: seizures or psychosis (having excluded drugs or other causes) Hematologic al disorder: haemolytic anemia or leucopenia (<4.0 x 109/L on two or more occasions), lymph openia (1.5 x 109/L on two or more occasions), thrombocytopenia (<100 x 109/L) Immunologica l disorder: raised anti-dsDNA antibody, anti-Sm anti- body, positive \201 nding of antiph ospholipid antibodies Antinuclear antibody in raised titre (in the absence of drugs known t o be associated with drug-induced lupus). Drug-induced lupus \200\224causative drugs include: \200 \200 \200 \200 \200 \200 Isoniazid Procainamide Hydralazine Minocycline Penicillamine Anticonvulsants. Further information Keane M, Lynch J Pleuropulmonary manifestations of SLE, Rare diseases 7 . Thorax 2000; 55: 159 \200\22366 192 CHAPTER 22 Connective tissue disease and the lung Polymyositis and dermatomyositis These are two separate disorders: \200 Polymyositis is an in \202 ammatory myopathy, causing symmetrical proximal muscle weakness Dermatomyositis is an in \202 ammatory myopathy with a characteristic rash Creatine kinas e levels raised up to 50 times normal. Antinuclear and myositis speci \201 c antibodies po sitive (Jo-1). Dermatomyositis is frequently associated with underlying malignancy, includi ng lung, esophagus, breast, colon, and ovary, so therefore needs thorough investigation. Pu lmonary complications are a common and frequent cause of death and occur in both conditions . Pulmonary \201 brosis in 20 \200\22330%. Patients present with dyspnoea. Mostly there i s basal \201 brosis \200\224usually similar to UIP, but can develop a more acute pneumoni tis resembling acute interstitial pneumonia (p 272). \200 \200 HRCT shows patchy consolidation and peripheral reticular pattern Histology may show feature s of organizing pneumonia and \201 brosing alveolitis, and therefore may have better resp onse to treatment Lung involvement frequently associated with antisynthetase antibodies May require treatment with steroids or cyclophosphamide \200 Ventilatory failure due to intercostal and diaphragmatic muscle weak- ness. Restrictive def ect on PFTs. Organizing pneumonia Poorer prognosis if associated with features of \201 br osis. Pulmonary hypertension secondary to lung disease. Pulmonary vasculitis causing haemop tysis or, rarely, alveolar hemorrhage. Aspiration pneumonia in 20%, associated with marked increase in mortality. Caused by dysphagia and pharyngeal muscle weakness and regurgitation . POLYMYOSITIS AND DERMATOMYOSITIS 193 Criteria for diagnosis of poly/dermatomyositis \200 Symmetrical proximal muscle weakness developing over weeks or months Elevated serum muscle enzymes, creatine kinase, and aldolase Typical EMG \201 ndings: \200 \200 \200 \200 Dermatological features of dermatomyositis: \200 \200 Myopathic potentials (low amplitude, short duration, polyphasic) Fibrillation Complex repet itive discharges Typical muscle biopsy \201 ndings \200\224endomysial in \202 ammation Gottron \200\231s papules, involving \201 ngers, elbows, knees, and medial malleoli Helio trope sign around the eyes Erythematous rash around back, shoulders, upper chest, and face \200 194 CHAPTER 22 Connective tissue disease and the lung Systemic sclerosis This disease affects women more than men (4:1), and often presents in th e \201 fth decade. It is a clinical diagnosis and there are 4 types: \200 Limited cutaneous (formerly known as CREST). Accounts for 60% of systemic sclerosis cases. Patients often have longstanding Raynaud \200\231s, and develop non-pitting oedema of the \201 ngers, which become \200\230sausage- shaped \200\231. Develop thick shiny skin after few weeks \200\223months. Later they can develop skin changes on the hands, face, and neck , microstomia, digital and facial telangectasias, intra- and subcutaneous calci \201 catio n, and oesophageal dysmotility (74%). Patients can also develop pulmonary \201 brosis (26 %), pulmonary hypertension (21%), cardiac (9%) and renal disease (8%), but less commonly th an in diffuse cutaneous disease Diffuse cutaneous Abrupt onset disease, with widespread sym metrical itchy painful swelling of \201 ngers, arms, feet, legs, and face, and associated constitutional symptoms. There is oedema, which is replaced by tight shiny skin, bound to underlying structures, within a few months. There is cutaneous thickening, as well as hypo- or hyperpigmentation. Raynaud \200\231s phenomenon is present, as well as skin sclerosis o n the trunk and upper arms, arthropathy, renal disease (18%), pulmonary \201 brosis (41%) , pulmonary hypertension (17%), and cardiac (12%) and GI disease (68%) Overlap syndromes, o r mixed connective tissue disease, have features of systemic sclerosis together with those of at least one other autoimmune rheumatic disease, such as SLE, rheumatoid arthritis, poly myositis. Over time other organ involvement may develop and evolve into a more de \201 ned disease Systemic sclerosis sine scleroderma Vascular or \201 brotic visceral features wi thout skin scleroderma. May or may not have Raynaud \200\231s phenomenon. May develop inter stitial lung disease, oesophagitis, arrhythmias, malab- sorption, pseudo-obstruction, renal failure. Less than 2% of cases. Systemic sclerosis pulmonary disease is the most common cause of death in patients with sys temic sclerosis. Pulmonary \201 brosis is seen at post-mortem in up to 75% of patients. A ntinuclear antibody is positive in 60%, of speckled or nucleolar type. Pulmonary involvemen t is seen particularly if Scl 70 antibody is present. Anticentromere antibodies, however, a re associated with reduced risk. \200 \200 \200 Present with dyspnoea and a history of Raynaud \200\231s Examination Signs of systemic scle rosis, \201 ne bibasal crepitations PFTs show restrictive defect and reduced kCO. Rapidly falling kCO is a poor prognostic sign. HRCT is performed if PFTs are abnormal. Mostly non- speci \201 c interstitial pneumonitis (NSIP) pattern on HRCT, but can be UIP pattern. May need open lung biopsy to con \201 rm diagnosis Treatment with steroids and cyclophosphamid e. A randomized controlled trial of oral cyclophosphamide vs. placebo in patients with acti ve alveolitis and scleroderma-related interstitial lung disease showed a modest but signi \201 cant effect on FVC, dyspnoea and quality of life (Taskin DP et al. NEJM 2006; 354: 265 5 \200\22366) SYSTEMIC SCLEROSIS 195 Prognosis Systemic sclerosis associated interstitial lung disease has better prognosis than pure UIP. This may be related to slower disease progression, rather than any greater respo nse to immunosuppressive treatment. 15% of patients have progressive and severe disease. As sociated increased risk of lung cancer. Pulmonary hypertension May be isolated or secondary to interstitial lung disease. Isolated pulmonary hypertension is characteristic of limited cutaneous disease, especially in those with cutaneous telangectasias and anticentromere antibodies. Pathologically similar to prim ary pulmonary hypertension. Sub-intimal cell proliferation, endothelial hyperplasia, and th e obliteration of small intrapulmonary vessels. \200 Present with dyspnoea, right ventricular hypertrophy, and right heart failure Diagnosis by echocardiography Treatment as for PPH (see p 392). May respond to prostacyclin infusions, o r may need transplant Prognosis better than for those with PPH. \200 Chest wall limitation by skin scleroderma over chest ( \200\230hide-bound chest \200\231). Organizing pneumonia See p 270. Aspiration pneumonia Uncommon and due to oesophageal dysmot ility. 196 CHAPTER 22 Connective tissue disease and the lung Sj gren \200\231s syndrome \200 In \202 ammation and destruction of primarily the salivary and lachrymal glands Keratoconj unctivitis sicca or xerostomia (dry eyes and dry mouth) is evidence of primary disease, but when associated with connective tissue disease, especially rheumatoid arthritis, is second ary Sj gren \200\231s Classical Sicca Syndrome includes dry eyes and mouth, and parotid or salivary gland enlargement Pulmonary involvement occurs in about 25%. Pleurisy Airways in \202 ammation Bronchial hyperresponsiveness, chronic bronchitis, and s mall airways disease. Mild abnormalities on PFTs, rarely signi \201 cant. Dry cough Atroph y of mucus gland in trachea and bronchi and lympho- plasmocytic in \201 ltrate (xerotrache a). Possibly a higher incidence of chest infections. Treatment: nebulized saline, physiothe rapy. Organizing pneumonia Rare. Diffuse lung disease Often asymptomatic, but may have coug h, dyspnoea, and crackles on examination. PFTs show a restrictive defect and lymphocytic in terstitial pneumonia (LIP) or UIP pattern on CT. Lymphoma Unusual, but is 40 times more com mon in Sj gren \200\231s syn- drome, especially in patients with high levels of immunoglob ulins, autoanti- bodies, and cryoglobulins. Usually B-cell lymphoma. Can mimic organizing p neumonia. ANKYLOSING SPONDYLITIS 197 Ankylosing spondylitis \200 Chronic in \202 ammatory disease causing spinal ankylosis with sacroiliac joint involvemen t 90% of Caucasian patients are HLA B27 positive. Pulmonary \201 brosis occurs in 2%, especially those with advanced disease. Typically bil aterally in the upper lobes. May develop cysts/cavities and become colonized with Aspergill us, which can require treatment. Pleural involvement Pleuritis and apical pleural thickenin g. Restrictive defect Due to \201 xed deformity of the thorax, limiting breathing and lea ding to respiratory failure due to nocturnal hypoventilation. Nocturnal NIV may be indicate d. 198 CHAPTER 22 Connective tissue disease and the lung Beh et \200\231s syndrome \200 Systemic vasculitis involving arteries and veins of all sizes with recur- rent oral geni tal ulceration and chronic relapsing uveitis, which can cause blindness Marked geographical distribution, with greatest prevalence in Turkey, Iran, and Japan Musculoskeletal, skin, n eurological, GI, and major artery and vein involvement. Pulmonary arterial aneurysms, arterial and venous thrombosis, and pulmonary infarcts in <5% . Recurrent haemoptysis is the main manifes- tation. This can be massive and fatal. Pulmona ry aneurysms are seen as non-cavitating shadows on CXR and con \201 rmed by CT. These are associ- ated with DVT, therefore making anticoagulation dif \201 cult due to possible haem optysis from the aneurysm. Pleural effusion rare. BEH \207ET S SYNDROME 199 Autoantibodies: disease associations Antinuclear antibody (ANA) +ve in SLE 99% Rheumatoid arthritis 32% Juvenile rheumatoid arthritis 76% Chronic active hepatitis 75% Sj gren \200\231s syndrome 68% Systemic sclerosis 64% Polymyositis Polyarteritis nodosa Myasthenia gravis Autoimmune thyroid disease Extensive burns Normal controls 0 \200\2232% Extractable nuclear antigen (ENA) (done by lab if ANA positive) Anti-double-stranded DNA \200\224SLE Anti Sm \200\224SLE Antitopoisomerase 1 \200\224diffuse scleroderma Anticentromere \200\224limited scleroderma Anti Scl-70 \200\224pulmonary \201 brosis in scleroderma Anti Jo-1 \200\224myositis Anti Ro \200\224Sj gren \200\231s, SLE, fetal heart block Anti RNP \200\224SLE, scleroderma, myositis, mixed connective tissue disease, and rheumatoi d arthritis Rheumatoid factor +ve in Rheumatoid arthritis 70 \200\22380% Sj gren \200\231s syndrome <100% Felty \200\231s syndrome <100% Systemic sclerosis 30% Still \200\231s disease Rarely positive Infective endocarditis <50% SLE <40% Normal controls 5 \200\22310% Also: Neoplasms after radio- or chemotherapy Hyperglobulinaemic states Dermatomyositis This page intentionally left blank 201 Chapter 23 Cor pulmonale 202 CHAPTER 23 Cor pulmonale De \201 nition Cor pulmonale is the traditional term for changes in the car- diovascular s ystem resulting from the chronic hypoxia (and usually hyper- capnia) of chronic lung diseas e, mainly pulmonary hypertension and \202 uid retention. It does not include similar chan ges seen in some left-sided disorders such as mitral incompetence. Causes and pathophysiolo gy Cor pulmonale can occur in most situ- ations where there is chronic hypoxia. \200 \200 \200 Most often in the setting of hypoxic and hypercapnic COPD Hypoventilation syndromes (scolio sis, neuromuscular diseases) Much less common when there is no associated rise in PaCO2 (e. g. with interstitial lung diseases). Cor pulmonale is often also referred to as \200\230right heart failure \200\231, which is misleading as the cardiac output in cor pulmonale is usually normal or high with increased peripheral perfusion (hence, the \200\230bounding pulse \200\231 of type II ventilatory fa ilure). The right ventricle (RV) can cope with much higher pres- sures than usually occur i n cor pulmonale, such as in idiopathic pulmonary arterial hypertension, if allowed time to adapt. In true right heart failure the RV fails to develop an adequate cardiac output, e.g. following right- sided MI, or pulmonary emboli that occlude a large proportion of the pulm onary vascular bed. This also produces a raised JVP, but in contrast there will be a low ca rdiac output and poor peripheral perfusion. Cor pulmonale results from the following sequence of events \200 \200 Lung disease causes hypoxia with cyanosis and often polycythaemia Hypoxia is sensed both wi thin the kidney and via the carotid body, generating increases in sympathetic activity and renal vasoconstriction Increased sympathetic activity (and other mechanisms) leads to renal retention of salt and water This extra salt and water is mainly held in the capacitance ve ssels (the large veins) often with a raised JVP If vascular permeability rises (particularl y when the PaCO2 rises, pro- ducing peripheral vasodilatation and an increase in capillary pressure), extra \202 uid accumulates in dependent tissues, mainly the ankles A raised JV P and ankle oedema in this setting are NOT due to impaired right ventricular function, but to \202 uid overload and increased vascular permeability. Patients often present with their \201 rst episode of ankle swelling during an exacerbati on of their COPD, when for the \201 rst time the PaCO2 rises and the PaO2 falls far enoug h to provoke the above events. Body weight may not actually rise suddenly with the onset of ankle oedema; however, the extra salt and water retained leading up to the exacerbation mo ves into the subcutaneous tissues, probably from the CO2-induced vasodilatation raising mea n capillary hydrostatic pressure. The hypoxia also raises the pulmonary artery pressure (PAP), but to modest levels for which the RV can easily compensate, particularly if it builds up slowly. Loss of pulmonary vascu lar bed from emphysema will also raise PAP. The ECG often shows right ventricular hypertrop hy. During an COR PULMONALE 203 exacerbation, extra hypoxia will produce further rises in PAP with which the RV usually cop es, helped by the raised JVP providing a larger pre-load to increase RV \201 lling. Exces sive diuresis can lead to a true fall in right-sided output due to inadequate \201 lling of the RV. Clinical features \200 \200 \200 The underlying disease causing the hypoxia, e.g. COPD/bronchiectasis Easily visible veins a nd a raised JVP Cyanosis and a suffused conjunctiva (polycythaemia and vessel dilatation fr om the raised CO2) Peripheral vasodilatation with a full \200\230bounding \200\231 pulse A nkle swelling and pitting oedema Right ventricular hypertrophy (sternal heave uncommon, mas ked by hyperin \202 ated lung between heart and chest wall; more often seen with the highe r pressures of IPAH) Tricuspid incompetence (not usually severe). \200 \200 Investigations \200 \200 \200 \200 CXR \200\224enlarged pulmonary arteries/underlying lung disease FBC \200\224may have associ ated polycythaemia Oximetry \200\224cor pulmonale is unlikely if awake SaO2 over 92% Blood gasses \200\224cor pulmonale progressively more likely as PaO2 drops below 8 kPa (equivalen t SaO2 8 91%), and PaCO2 rises above 6 kPa ECG \200\224may indicate right axis deviation, p pulmonale (right atrial hyper- trophy), and right bundle branch block Echo \200\224dilated or hypertrophied RV, tricuspid regurgitation, estimate of PAP, and exclude other diagnoses such as a patent ASD Overnight oximetry \200\224to reveal unexpected degrees of hypoxia, e .g. from OSA or diaphragm paralysis. Management Minimal ankle oedema needs no treatment. \200\230Trimming \200\231 the ankles t o normal is unnecessary and may reduce RV output by reducing \201 lling. If the oedema is more substantial then the following may help: \200 \200 \200 Treat underlying condition to raise PaO2 and lower PaCO2 Raise PaO2 through added oxygen, p rovide long-term oxygen at home In hypoventilation syndromes, home overnight NIV likely to be the correct management Promote a limited diuresis with judicious use of diuretics Always elevate legs when sitting. \200 In general, \200\230cor pulmonale \200\231 is over-treated. It is usually a relatively har mless by-product of hypoxia, rather than a problem in its own right. Treating the blood gas disturbance, and making it easier for the patient to get his shoes on, are the main therap eutic aims. The long-term oxygen trials showed that improving the PaO2 was useful, not that lowering the pulmonary artery pressure was important. Further information Stewart AG et al. Hormonal, renal, and autonomic nerve factors involved in the excretion of sodium and water during dynamic salt and water loading in hypoxaemic c hronic obstructive pulmonary disease. Thorax 1995; 50: 838 \200\22345 This page intentionally left blank 205 Chapter 24 Cystic \201 brosis General principles 206 CF pulmonary sepsis: etiology 208 CF pulmonary sepsis antibiotics: 1 210 CF pulmonary sepsis antibiotics: 2 212 IV antibiotic administration 214 Management of an exacerbation 216 Other pulmonary interventions 218 Other pulmonary disease 220 Non-pulmo nary disease 222 Other issues 224 Seeing the patient with CF in clinic 226 206 CHAPTER 24 Cystic \201 brosis General principles De \201 nition and pathophysiology \200 Multisystem disease due to mutations in the gene encoding for the cystic \201 brosis tran smembrane conductance regulator (CFTR), a complex chloride channel CFTR is essential for re gulating salt and water movement across membranes Faulty regulation causes viscous secretio ns In the lungs, these secretions result in colonization with pathogenic bacteria, causing a massive in \202 ammatory response, including elastase release. This contributes to lung damage and subsequent development of irreversible bronchiectasis In the pancreas, the exocr ine ducts become blocked by secretions, leading to pancreatic enzyme insuf \201 ciency, pa ncreatic destruction, and diabetes mellitus. \200 Genetics \200 \200 \200 Autosomal recessive Gene found on the long arm of chromosome 7 Carrier frequency of this ge ne in Caucasians 1 in 25. 1 in 2500 UK live births have cystic \201 brosis CF is rare in Afro-Caribbeans, but is seen in patients of Asian origin in the UK and USA Heterozygote adv antage through resistance to E. coli diarrhea and cholera has probably led to persistence o f CFTR mutations, despite the lethal homozygous form More than 1500 different mutations in the CFTR gene are recognized to cause clinical disease The most common mutation is ZF508, w hich accounts for around 67% of CF alleles in the UK and northern Europe. This is a deletio n of 3 nucleotides resulting in the omission of a single amino acid, phenylalanine, at the 508 residue 13 other mutations have a frequency of greater than 1%, accounting for 85% of C F alleles altogether. These can be effectively screened for. They include G542X (3.4%), G55 1D (2.4%), W1282X (2.1%), and 3905insT (2.1%) Different mutations may be associated with pa rticular clinical sub- groups. The phenotype \200\223genotype relationship is closest for p ancreatic disease Non-CFTR \200\230modi \201 er \200\231 genes (such as TNFA, mannose bin ding lectin, and A1-antitrypsin), as well as environmental factors, probably further in \202 uence the clinical picture and account for phenotypic variation. Screening In the UK, neonatal heel-prick for immunoreactive trypsin measurement is now offe red routinely as part of a new national screening program. Prenatal second trimester fetal ultrasound may identify pre- sence of echogenic bowel, which can occur in CF. These babies are then screened at birth. Those with relatives with CF are advised to have pre- conceptio n CF genotyping, as are the partners of a patient with CF. GENERAL PRINCIPLES 207 Diagnosis Patients are usually diagnosed with CF as neonates or children (genetic screening , family history, failure to thrive, meconium ileus, rectal prolapse, cough, recurrent ches t infections). Diagnosis is based on compat- ible clinical \201 ndings, with biochemical or genetic con \201 rmation. The sweat chloride test is an important laboratory test, part icularly in children. Some patients are diagnosed with CF in adult life. They usually have different alleles leading to a milder phenotype. Management The ongoing care of CF patients moves to the adult CF center around the age of 16 \200\22318 (often when the patient leave s school), although a period of transitional care may occur between ages 14 \200\22316. A m ultidisciplinary team approach is recommended, consisting of respi- ratory physician, speci alist nurse, physiotherapist, pharmacist, dietician, and psychologist, with regular additio nal input from gastroenterology and endocrine teams. This transition can be a dif \201 cult time, as the patient begins to take more responsibi lity for their care and treatment. Some may have periods of rebelling, not taking medicatio ns or performing physiotherapy, despite recognizing the need to do so. Improved treatment and nutrition of CF patients has led to an increase in median survival, to around 30 years. The predicted lifespan for a baby born with CF now is 42 years. The main management issues for the adult CF patient are: Lung disease \200 \200 Maintaining lung function Monitoring lung bacteriology, including screening for multi-resis tant and transmissible organisms Consideration of referral for heart \200\223lung or liver transplant, if and when appropriate