Oxford Case Histories in Respiratory Medicine OXFORD CASE HISTORIES Series Editors Peter Rothwell and Sarah Pendlebury Published: Neurological Case Histories (Sarah Pendlebury and Peter Rothwell) Oxford Case Histories in Gastroenterology and Hepatology (Alissa Walsh, Otto Buchel, Jane Collier, and Simon Travis) Oxford Case Histories in Respiratory Medicine (John Stradling, Andrew Stanton, Najib Rahma n, Annabel Nickol, and Helen Davies) Upcoming: Oxford Case Histories in Cardiology (Colin Forfar, Javed Ehtisham and Rajkumar Rajendram) O xford Case Histories in Nephrology (Chris Pugh, Chris O \200\231Callaghan, Aron Chakera, Ri chard Cornall and David Mole) Oxford Case Histories in Rheumatology (Joel David, Anne Mille r, Anushka Soni and Lyn Williamson) Oxford Case Histories in Stroke and TIA (Sarah Pendlebu ry and Peter Rothwell) Oxford Case Histories in Respiratory Medicine John Stradling Professor of Respiratory Medicine, Oxford University, Consultant Physician, Oxford Center for Respiratory Medicine, Churchill Hospital, Oxford Andrew Stanton Specialist Registrar in Respiratory Medicine Oxford Center for Respiratory M edicine Churchill Hospital, Oxford Najib Rahman Specialist Registrar and MRC Training Fellow Oxford Center for Respiratory Med icine Churchill Hospital, Oxford Annabel Nickol Clinical Lecturer in Respiratory Medicine Oxford Center for Respiratory Medi cine Churchill Hospital, Oxford Helen Davies Specialist Registrar in Respiratory Medicine Oxford Center for Respiratory Med icine Churchill Hospital, Oxford 1 1 Great Clarendon Street, Oxford OX2 6DP Oxford University Press is a department of the Unive rsity of Oxford. 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T he authors and the publishers do not accept responsibility or legal liability for any error s in the text or for the misuse or misapplication of material in this work. Except where ot herwise stated, drug dosages and recommendations are for the non-preg- nant adult who is no t breast-feeding. A note from the series editors Case histories have always had an important role in medical education, but most published m aterial has been directed at undergraduates or residents. The Oxford Case Histories series aims to provide more complex case-based learn- ing for clinicians in specialist training an d consultants, with a view to aiding preparation for entry and exit-level specialty examina tions or revalidation. Each case book follows the same format with approximately 50 cases, each comprising a brief clinical history and investigations, followed by questions on diffe rential diagnosis and management, and detailed answers with discussion. All cases are peer- reviewed by Oxford consultants in the relevant specialty. At the end of each book, cases ar e listed by mode of presentation, etiology and diagnosis. We are grateful to our colleagues in the various medical specialties for their enthusiasm a nd hard work in making the series possible. Sarah Pendlebury and Peter Rothwell Quotes on the first book in the series \200\223 \200\234Neurological Case Histories \200 \235 \200\234I recommend this excellent volume highly this book will enlighten and ente rtain consultants, and all readers will learn something. \200\235 Lancet Neurology 2007; 6: 951 \200\234This short and well-written text is \200 . designed to enhance the reader \200 \231s diag- nostic ability and clinical understanding \200 . A well documented and practic al book \200\235 European Journal of Neurology 2007; 14: e19 This page intentionally left blank Introduction Postgraduate medical education has changed considerably over the last 30 years. There is gr eater emphasis on structured learning, but apprenticeship time has decreased. Thus speciali st registrars may reach the end of their training without having seen cases of either rare diseases, rare presentations of common diseases or unusual problems in association with com mon diseases. Most phy- sicians learn from cases they have seen. This collection of cases i s a second-best alternative, providing vignettes that hopefully will come to mind when a si milar case is encountered in the future. The cases are not meant to comprehensively cover the \200\230syllabus \200\231 of a specia list registrar in respiratory medicine, but are selected for their interest, or to eluci- d ate points that the authors feel are important but may be under-appreciated. The style of p resentation thus inevitably varies depending on the type of message and some of the problem s discussed have no right answer, ours may well be disputed! We hope the question-and-answer format will keep the reader on their toes and make reading through the cases more fun. This page intentionally left blank Acknowledgements Many people have given their time to read through these cases and correct errors or improve clarity. We are very grateful for their input; in particular Rachel Benamore has provided considerable help with the radiology, and Rolf Smith read through all the cases to provide us with invaluable help. These are the individuals who reviewed one or more cases for us: L esley Bennett, Malcolm Benson, Di Bilton, Steve Chapman, Sonya Craig, Ling-Pei Ho, Rob Davi es, Colin Forfar, Maxine Hardinge, Robin Howard, Gary Lee, Raashid Luqmani, Lorna McWilliam , Grace Robinson, Rana Sayeed, Claire Shovlin, Catherine Swales, Catherine Thomas, Chris Wi nearls, and John Wrightson. Needless to say any errors remain our responsibility. This page intentionally left blank Contents Abbreviations xiii Normal ranges xvi Cases 1 \200\22344 1 List of cases by etiology 387 List of cases by diagnosis 388 This page intentionally left blank Abbreviations AAFB ABG ABPA Acid- and alcohol-fast bacilli Arterial blood gasses Allergic bronchopulmonary aspergillosi s Angiotensin converting enzyme Anti-nuclear antibody Anti-nuclear cytoplasmic antibody Adu lt respiratory distress syndrome Atrial septal defect Arteriovenous malformation Bronchoalv eolar lavage Benign asbestos-related pleural effusion Base excess Body mass index (kgs/ met er 2 ) Bone marrow transplant Brain natriuretic peptide bronchiolitis obliterans Beats per minute Calcium Capillary blood gasses Congenital cystic adenomatoid malformation Contrast-e nhanced transthoracic echo Cystic fibrosis Cystic fibrosis transmembrane conductance regula tor Chronic lymphatic leukemia Cryptogenic organizing pneumonia Continuous positive airway pressure C-reactive protein Computerized tomography CTEPH Chronic thromboembolic pulmonary hypertension Computerized tomographic pulmonary angiogram Common variable immunodeficiency Chest radiograph Diastolic blood pressure Direct Coombs te st Deoxyribonucleic acid Directly observed therapy Diffuse panbronchiolitis Driver vehicle licensing authority Deep vein thrombosis Enzyme immunoassay Emphysema-like changes extralob ar sequestration extrapleural pneumonectomy Epworth sleepiness score Forced expiratory volu me in one second Functional residual volume Forced expiratory volume Graft-versus-host-dise ase Haematoxylin and Eosin Hemoglobin Bicarbonate Hypereosinophilic syndrome Heavy goods ve hicle Hereditary haemorrhagic telangiectasia Human immunodeficiency virus Human leukocyte a ntigen Hypersensitivity pneumonitis Hepatopulmonary syndrome CTPA CVID ACE CXR DBP DCT DNA DOT DPB DVLA ANA ANCA ARDS ASD AVM BAL BAPE DVT EIA ELCs ELS EPP ESS FEV 1 BE BMI BMT BNP BO BPM Ca ++ CBG CCAM FRC FVC GVHD H&E Hb [HCO 3 ] HES HGV HHT CETTE CF CFTR CLL COP HIV CPAP HLA HP HPS CRP CT ABBREVIATIONS xiv HRCT High resolution computerized tomography Heart rate Inhaled corticosteroid Interleukin 1 int ralobar sequestration International normalized ratio Interstitial pulmonary fibrosis Inferi or vena cava Jugular venous pressure Potassium Carbon-monoxide transfer coefficient Lymphan gioleiomyomatosis Langerhans cell histiocytosis Lactate dehydrogenase Liver function tests Lymphoid interstitial pneumonia Long-term oxygen therapy Left ventricle Left ventricular sy stolic function Mycobacteria avium complex Microscopy, culture and sensitivity Medium-chain triglycerides Mean corpuscular volume Multi-drug resistant TB Monoclonal gammopathy of unk nown significance Myocardial infarction Myeloperoxidase Multiple sleep latency test Mainten ance of wakefulness test Sodium Non-steroidal anti- inflammatory agent National Institute f or Health and Clinical Excellence Non-specific interstitial pneumonia Non-tuberculous mycob acteria OSA OSAS Obstructive sleep apnoea Obstructive sleep apnoea syndrome Oxford sleep resistance test Pul monary artery Partial pressure of arterial carbon-dioxide Partial pressure of arterial oxyg en Pulmonary artery pressure Pulmonary arteriovenous malformations Primary ciliary dyskines ia Protein creatinine ratio Peak expiratory flow rate Pulmonary hypertension Patent foramen ovale Pulmonary function tests Post-nasal drip or paroxysmal nocturnal dyspnoea Primary sp ontaneous pneumothorax Rheumatoid associated interstitial lung disease Airway resistance (f rom body box) Respiratory bronchiolitis \200\223 interstitial lung disease Re-expansion pul monary oedema Residual volume/Right ventricle Arterial oxygen saturations Systolic blood pr essure Shortness of breath Superior vena cava Thyroxine Tuberculosis Transbronchial biopsy Total lung capacity Carbon-monoxide transfer factor Tumor/nodes/metastases classification HR ICS IL1 ILS INR IPF IVC JVP K + K CO OSLER PA P a CO 2 P a O 2 PAP PAVM PCD PCR PEFR PH PFO PFTs PND LAM LCH LDH LFTs LIP LTOT LV LVSF PSP RA-ILD MAC MCS RAW RBILD MCT MCV MDR-TB MGUS RPO RV S a O 2 SBP SOB SVC T4 TB TBB TLC TL CO MI MPO MSLT MWT Na + NSAID NICE NSIP TNM NTM SYMBOLS AND ABBREVIATIONS xv TPN U&Es UACS Total parenteral nutrition Urea and electrolytes Upper airway cough syndrome Usual intersti tial pneumonia USS VATS VCD VTE V/Q Ultrasound scan Video-assisted thoracoscopy Vocal cord dysfunction Venous thrombo-embolism Ventilation/perfusion UIP Normal ranges Lower limit Upper limit units Hb (men) Hb (women) MCV WCC Neutrophils Lymphocytes Eosinophils Platelets PTT APTT ESR Na K Urea Creatinine Bilirubin AST ALT ALP Albumin GGT (men) GGT (women) Ca (corr) PO 4 Glucose (fasting) CRP ACE 1 anti trypsin PSA PaO 2 PaCO 2 pH Base excess Bicarbonate IgG IgA IgM IgE 13 11.5 83 4 2 1 0.02 18 15 105 11 7 4 0.5 g/dL g/dL fL \22710 9 /L \22710 9 /L \22710 9 /L \22710 9 /L \22710 9 /L s s mm/hr mmo l/L mmol/L mmol/L umol/L umol/L IU/L IU/L IU/L g/L IU/L IU/L mmol/L mmol/L mmol/L mg/L IU/L mg/dL ng/mL kPa kPa 150 10 22 0 135 400 14 34 about half the age 145 5 6.7 3.5 2.5 70 3 3 10 75 35 11 7 2.12 0.8 3.5 0 18 107 0 12 4.7 7.36 150 17 35 45 250 50 51 33 2.62 1.45 5.5 8 55 209 4 14 5.9 7.44 2 27 13 3 2.5 \210\2222 23 6 0.8 0.4 5 meq/L meq/L g/L g/L g/L kU/L 120 Case 1 A 42-year-old lady was referred for respiratory review with a history of asthma, which had become difficult to control over the last 3 years, with increased nocturnal cough and peak flow variability. She had received multiple courses of oral antibiotics and steroids to whi ch she would briefly respond, and was on a long-term combined inhaled steroid and long-acti ng beta agonist. She used a nasal steroid for nasal polyps. She had not moved house or chan ged jobs, she worked as a gardener and had no pets. Questions 1a) What reasons could explain this deterioration after many years of good control? CASE HISTORIES IN RESPIRATORY MEDICINE 2 Answers 1a) What reasons could explain this deterioration after many years of good control? There are multiple reasons to fail to respond to asthma therapy, including a poor inhaler t echnique or adherence to therapy. Reasons for deteriora- tion in symptoms after good contro l include: \227\206 Development of oesophageal reflux \227\206 New exposure to asthma triggers, e.g. house-dust-mite, cat fur, pollen or occupational exposure \227\206 New psychological or social pressure \227\206 Alternative diagnoses, such as the development of allergic bronchopul- monary aspergillosis (ABPA) or Churg \200\223Strauss syndrome \227\206 Gain in weight. Investigations showed \227\206 Full blood count: Hb, 13.5g/dL \227\206 WCC, 7.29 \227 10 9 /L \227\206 Eosino phils, 3.21 \227 10 9 /L \227\206 Platelets, 362 \227 10 9 /L \227\206 Total IgE, 620 n g/ml (normal range 5 \200\223120) \227\206 Aspergillus RAST (IgE), strongly positive \227\206 Aspergillus precipitins (IgG), 2 lines (where 1 line = weakly positive and 6 = strongly positive) \227\206 Sputum culture, mucoid Pseudomonas aeruginosa \227\206 CF genetic screening, negative for common CF mutations. Questions 1b) What do the CXR and CT scan in Fig. 1.1 show? 1c) What diagnosis do investigations support? 1d) What are the typical clinical features of this condition? 1e) Discuss treatments options for this lady. CASE 1 3 (a) (b) Fig. 1.1 (a) CXR and (b) CT chest. CASE HISTORIES IN RESPIRATORY MEDICINE 4 Answers 1b) What do the CXR and CT scan in Fig. 1.1 show? The CXR shows hyper-expanded lung fields, with widespread bronchiec- tatic changes. The CT slice shows dilated airways, much larger than the adjacent blood vessel, in keeping with br onchiectasis. There is also \200\230tree in bud nodularity \200\231, which may be suggesti ve of small airway chronic or atypical infection. Tree-in-bud nodularity Dilated airways Fig. 1.2 Portion of CT-chest illustrating features in keeping with allergic bronchopulmonar y aspergillosis. 1c) What diagnosis do investigations support? Investigations support a diagnosis of allergic bronchopulmonary aspergil- losis, ABPA. Atop ic patients with asthma and cystic fibrosis with IgE- mediated allergy to inhaled Aspergill us spores are vulnerable to this condition. They may develop IgE and IgG reactions to Asper gillus in the airways, provoking mucous plugging with distal consolidation, and then ABPA, with inflammatory damage to the airways and resultant bron- chiectasis. Damp conditions, co mposting organic material and thunder- storms are associated with high Aspergillus spore co unts, and so may lead to exacerbations. Since simple atopic asthma is at one end of a conti nuum, with ABPA at the other, there is no single diagnostic test that defines the transitio n. The presence of the features in Box 1.1 would support the diag- nosis, with the first fo ur being the most important. Many asthmatics and patients with cystic fibrosis have one or more findings suggestive of ABPA, but do not fulfill all criteria listed. ABPA is a complex hypersensitivity reaction, often in patients with asthma or cystic fibros is that occurs when bronchi become colonized by Aspergillus . CASE 1 5 Box 1.1 Diagnostic features of ABPA \227\206 Longstanding history of asthma \227\206 Immediate positive IgE reaction to Aspergillus on skin testing, or on serum testing using RAST (radioallergosorbent test) \227\206 Precipitating serum IgG antibodies to Aspergillus fumigatus \227\206 Central bronchiectasis on chest CT \227\206 Peripheral blood eosinophilia \227\206 Serum total IgE concentration elevated > 1000ng/mL \227\206 Flitting lung infiltrates on CXR or chest HRCT. Repeated episodes of bronchial obstruction, inflammation, and mucoid impaction can lead to bronchiectasis, fibrosis and respiratory compro- mise. It is thought healthy, unaffected in dividuals are able to effectively eliminate fungal spores. They have low levels of IgG agai nst fungal anti- gens in the circulation, and low anti-fungal secretory IgA in bronchoal- v eolar fluid. In contrast, exposure of atopic individuals to fungal spores or mycelial fragm ents results in the formation of IgE and IgG antibodies. Aspergillus responsive T-cells gen erate the cytokines interleukin (IL)-4, IL-5 and IL-13, which account for the eosinophilia and raised IgE in ABPA. Aspergillus colonization of the asthmatic airway leads to vigorous IgE- and IgG-mediated immune responses superimposed on the asth- matic milieu. In spite of these vigorous responses in ABPA, the fungus is able to colonize the airway and cause recur rent symptoms. Proteolytic enzymes are released by Aspergillus as part of its exophytic fee ding strat- egy, and these enzymes may in theory damage airway walls. However, exuberant ho st defense mechanisms are thought to be the dominant method of damage, hence there is a goo d response to steroids. Spores and hyphae (indicating germination of the spores in the airw ay) are some- times seen on direct microscopy, and Aspergillus is cultured from sputum in u p to two-thirds of patients with ABPA. As in most cases of ABPA, the patient in this case h ad a background history of atopic asthma. 1d) What are the typical clinical features of this condition? Typical clinical features of ABPA are long-standing asthma with a more recent deterioration , complicated by recurrent episodes of bronchial obstruction and expectoration of brownish mucous plugs, fever, malaise, peripheral blood eosinophilia and sometimes episodic haemopty sis. CASE HISTORIES IN RESPIRATORY MEDICINE 6 Wheezing is not always present, and some patients present with asympto- matic \200\230flit ting \200\231 pulmonary consolidation. 1e) Discuss treatment options for this lady. Treatment of ABPA involves optimal care of bronchiectasis and asthma, plus early use of ora l steroids and consideration of itraconazole with drug level monitoring where this is avail able. This needs to be prescribed for 3 to 6 months (regular liver function tests are neede d as the drug may be hepatotoxic) and the IgG levels to Aspergillus should fall with fungal load reduction. Inhaled steroids may help control symptoms of asthma, but do not have docu mented efficacy in preventing acute episodes of ABPA. Further reading Denning D , O \200\231Driscoll B , Hogaboam C , Bowyer P and Niven RM ( 2006 ). The link be tween fungi and severe asthma: a summary of the evidence . Eur Respir J ; 27 : 615 \200\223 626 . Stevens DA , Schwartz HJ , Lee JY , Moskovitz BL , Jerome DC , Catanzaro A et al. ( 2000 ). A randomized trial of itraconazole in allergic bronchopulmonary aspergillosis . New Eng J Med ; 342 : 756 \200\223 762 . Case 2 A 77-year-old lady was referred with progressive breathlessness over 3 years. She was breat hless walking 100 yards on the flat and could not manage stairs. There were no other respir atory symptoms. Past history was of myocardial infarction (MI) in 1984, and duodenal ulcer 1988. She had stopped smoking after her MI, with a prior 40 pack year smoking history. Her medication con- sisted of simvastatin, lisinopril, furosemide, aspirin, amiodarone, salbuta mol and omeprazole. All of her cardiac medications were commenced post-MI. She kept no pets . On examination there was central cyanosis, finger clubbing and resting oxygen saturations of 83% on room air. JVP was not elevated and there was no peripheral oedema. Cardiac exami nation revealed an aortic scle- rotic murmur and respiratory examination revealed bibasal f ine inspiratory crackles in the lower zones. Abdominal and musculoskeletal examination was unremarkable. Investigations \227\206 Hb 14.3g/dL, WCC 5.94 \227 10 9 /L (eosinophils 0.18 \227 10 9 /L), platelets 145 \227 10 9 /L \227\206 ESR, 48mm/h \227\206 U&Es, normal \227\206 Bilirubin 39 mol/L, ALT 18 IU/L, ALP 308 IU/L \227\206 Albumin, 27g/L \227\206 Rheumatoid factor, 69.4U (<10, negative; 10 \200\22330, borderline; >30, posi- tive) \227\206 ANA, anti-smooth muscle antibody, anti-mitochondrial antibody, and anti-gastric parietal cell antibody: negative \227\206 Alpha 1 antitrypsin, 185mg/dL (normal 107 \200\223209 mg/dL) \227\206 ABG (on ai r), PaO 2 6.7 kPa, PaCO 2 4.17 kPa, [HCO 3 ] 23.3 mol/L, pH 7.45 \227\206 ECG, normal \227\206 Abdominal USS, liver appeared slightly enlarged with an irregular outline. Spleen was also slightly irregular. Pancreas and kidneys were normal. CASE HISTORIES IN RESPIRATORY MEDICINE 8 Table 2.1 Pulmonary function tests Measured % Predicted FEV1(L) 2.0 131 FVC(L) 2.8 144 FEV1/FVC(%) 71 FRC(L) 2.8 110 RV(L) 1.9 97 TLC(L) 4.7 108 VA(L) 3.6 82 TLCO(mmol/min/kPa) 2.05 34 KCO(mmol/min/kPa/L) 0.57 41 Fig. 2.1 CXR. CASE 2 9 (a) (c) (b) (d) Fig. 2.2 HRCT thorax. Fig. 2.3 CT of upper abdomen. Questions 2a) Interpret the lung function tests. 2b) Interpret the CXR. 2c) Interpret the CT images. 2d) What specific diagnoses can be made from the above investigations? 2e) What further diagnoses should be considered, what simple bedside test can help with the differential, and what further investigations are needed? CASE HISTORIES IN RESPIRATORY MEDICINE 10 Answers 2a) Interpret the lung function tests . The pulmonary function tests (PFT \200\231s) show slightly supra-normal dynamic lung volume s (although in more elderly patients prediction of \200\230normal \200\231 is less well de fined), but no evidence of any obstructive or restric- tive ventilatory defect. In addition the static lung volumes are also normal. There is an isolated marked reduction in gas tran sfer but the cause cannot be deduced. 2b) Interpret the CXR . The CXR ( Fig. 2.1 ) shows bilateral basal reticulonodular opacities. Otherwise there is no focal lung lesion, the heart size and mediastinal contours are normal. The right hemi-diap hragm is slightly flat in appearance. 2c) Interpret the CT images . The HRCT ( Fig. 2.2 ) shows moderate emphysematous changes most marked in the mid and upper zones ( Fig. 2.4b ). There are minor degrees of subpleural reticulation and honeycombing a t both bases ( Fig. 2.4a ). On the abdominal image (Fig. 2.3 ) the liver has an irregular m argin and there is splenomegaly. There is also ascites present. (a) (b) Fig. 2.4 Enlarged portions of HRCT. CASE 2 11 2d) What specific diagnoses can be made from the above investigations? CT diagnoses ( Fig. 2.4 ) are: \227\206 Emphysema \227\206 Interstitial lung disease (likely idiopathic pulmonary fibrosis, UIP pattern on CT) \227\206 Cirrhosis with portal hypertension. At this point the investigations are not compatible with a unifying respiratory diagnosis. The degree of emphysema and interstitial lung dis- ease identified on the CT seems out of p roportion to the hypoxaemia on the blood gasses. Furthermore, the lung function shows no ev idence of obstructive or restrictive defects. The isolated reduction in gas transfer could be due to emphysema or early interstitial lung disease, but again this is marked (41% predi cted) and one would perhaps expect greater physi- ological disturbance were either, or both , of these two diagnoses primarily responsible. The finger clubbing could be caused by the interstitial lung disease or possibly cirrhosis. The presence of honeycombing suggests esta blished fibrosis, the precise cause of which cannot be absolutely cer- tain. Amiodarone cou ld potentially be implicated and it would not be unreasonable for this to be stopped, but a gain it is certainly unlikely to be the whole story. 2e) What further diagnoses should be considered, what simple bedside test can help with the differential, and what further investigations are needed? A full explanation for her respiratory failure and markedly low gas transfer is needed. Giv en the presence of cirrhosis with ascites, the hepatopulmo- nary syndrome with pulmonary ar teriovenous malformations (AVMs) is the most likely unifying diagnosis. An alternative, but less likely explana- tion, would be chronic pulmonary thromboembolic disease. A simple bed side test to help sort this out would be to investigate any postural changes in oxygen satu rations. In pulmonary AVMs, oxygen saturation may fall on assuming an upright posture (orth odeoxia). Confirmatory investigations would therefore be: (i) Whole chest CT pulmonary angiogram. This showed no evidence of pulmonary emboli. Increa sed nodularity was seen peripherally at both bases (arrows, Fig. 2.5 ), which would be cons istent with arteriovenous malformations secondary to hepatopulmonary syndrome. CASE HISTORIES IN RESPIRATORY MEDICINE 12 Fig. 2.5 Enlarged portion of CTPA. (ii) \200\230Shuntogram \200\231 using 99m technicium-microaggregated albumin lung perfusi on scanning. This demonstrated renal uptake of 17% of radi- olabelled microalbumin administ ered, consistent with a shunt (see Case 40). Hepatopulmonary syndrome (HPS) This is defined by the triad of liver disease (most commonly cirrhosis, although cases with acute and chronic non-cirrhotic hepatitis have been described), intrapulmonary vasodilatio n at capillary and pre-capillary level (producing right to left shunting) and impaired arte rial oxygenation. Pathogenesis is unclear but is thought to relate to increased pulmonary p roduction of nitric oxide in liver disease. HPS should be considered in any patient with li ver disease who has unexplained breathlessness and arterial deoxygenation. The phenomenon o f orthodeoxia, a significant decrease of PaO 2 or SaO 2 going from supine to upright positi on, is explained by postural redirection of pul- monary blood flow to mainly the bases wher e the AVMs predominate; this increases the effective shunting compared to a horizontal post ure, where pul- monary blood flow is more evenly distributed. Because these dilated vessels are still adjacent to alveoli, and not anatomically separate vascular malformations, they do not behave quite as true shunts. However, hypoxia develops through a mechanism called \200\230diffusion \200\223perfusion impairment \200\231, whereby oxygen mol- ecules cannot diffuse in time to the center of dilated capillaries from adjacent alveoli to oxygenate hem oglobin in erythrocytes at the center of the stream of blood. It is thought this is also ag gravated by a hyperdynamic circulation, resulting in a shorter transit time through the lun gs for the red cell. This also explains why increasing inspired oxygen concentration raises the Pa O 2 more than would be expected with a true shunt. CASE 2 13 Diagnosis of HPS is best made by either contrast-enhanced transthoracic echo (CETTE) or 99m technicium-microaggregated albumin perfusion scanning. With CETTE, microbubbles (injected peripherally) appearing abnormally in the left atrium, after at least three cardiac cycles, implies an intrapulmonary shunt (immediate appearance in the left heart implies intra-card iac right-to- left shunt). With isotope perfusion scanning, the pulmonary vasculature shoul d trap the majority (94 \200\22397%) of the 20 \200\22360 m-diameter albumin microaggregat es, with extrapulmonary uptake only appearing in brain, liver or kidney if there is right-t o-left shunting. In HPS, the shunt ratio is over 10% and can be as high as 70%, but this wi ll not differentiate between intrapulmonary or intra-cardiac shunting, of course. Patients with HPS and cirrhosis have markedly reduced survival compared to those without (m edian survival 10.6 versus 40.8 months), and HPS is recognized as an added indication for l iver transplant in some centers. Some case reports demonstrate complete resolution of HPS f ollowing transplant, but no other treatment is of proven benefit. There are isolated case r eports of benefit from coil embolization and transjugular intraheptic portosystemic shuntin g. Supplementary oxygen can improve oxygenation and symptoms. Further reading Shenk P ( 2005 ). The hepatopulmonary syndrome . ERJ Monograph 34 , chapter 7 . Case 3 A 41-year-old woman presented with a 4-month history of shortness of breath on exertion, wi th no associated cough or systemic symptoms. Her previous medical history included Raynaud \200\231s phenomenon, and 18 months dysphagia and dyspepsia. A recent barium swallow demons trated severe oesophageal dysmotility and inco-ordination of the gastro-oesophageal junctio n. She smoked (20-pack year smoking history), and was overweight (body mass index 43). Exam ination was normal, apart from skin changes of hands and mouth ( Fig. 3.1 ). Pulmonary func tion tests ( Table 3.1 ), a CT chest ( Fig. 3.2 ) and an echocardiogram were performed. She had a modestly elevated pulmonary arterial pressure at 35mmHg. Fig. 3.1 Hands, and mouth during maximal mouth opening. Table 3.1 Pulmonary function tests Measured % Predicted 94 \200\22396% SaO2 FEV1(L) 1.9L 71 FVC(L) 2.4L 75 FEV1/FVC ratio 82% FRC(L) 2.2L 79 RV(L) 1.6L 92 TLC(L) 3.9L 83 TLCO(mmol/min/kPa) 4.51 50 KCO(mmol/min/kPa/L) 1.43 76 CASE 3 15 Fig. 3.2 CT chest. Questions 3a) Describe the changes shown in Figs 3.1 and 3.2 . 3b) Describe the abnormalities shown by the pulmonary function tests. List two causes of th e restrictive defect observed in this patient and suggest how you could tell which one pred ominates. 3c) Suggest a unifying diagnosis. CASE HISTORIES IN RESPIRATORY MEDICINE 16 Answers 3a) Describe the changes shown in Figs 3.1 and 3.2. Skin changes: Fig. 3.1 shows changes consistent with scleroderma, with skin tightening, ind uration and thickening around finger tips and mouth. HRCT changes; Fig. 3.2 shows subtle su b-pleural ground glass opacification, with- out significant associated reticulation or trac tion bronchial dilation. 3b) Describe the abnormalities shown by the pulmonary function tests. List two causes of th e restrictive defect observed in this patient and suggest how you could tell which one pred ominates. Pulmonary function tests ( Table 3.1 ). Restrictive spirometry is demon- strated, with a ra ised FEV 1 /FVC ratio, proportional reduction of static lung volumes, and low KCO. Two pote ntial causes of this patient \200\231s restric- tive spirometry are interstitial lung disea se and obesity. If obesity were the primary cause and the underlying lungs were normal, the n KCO would be supra-normal (Hart et al . 2002). However, in this case the KCO is signifi- cantly reduced at 76% predicted, which implies the underlying lung parenchyma is abnormal a nd interstitial lung disease predominates. 3c) Suggest a unifying diagnosis. Systemic sclerosis. Scleroderma, Raynaud \200\231s phenomenon, oesophageal dysmotility and possible early interstitial lung disease are suggestive of diffuse cutaneous systemic scler osis. Systemic sclerosis is a generalized connective tissue disorder occurring more commonl y in women. CASE 3 17 Question 3d) There are two subsets of systemic sclerosis: limited cutaneous systemic sclerosis and d iffuse cutaneous systemic sclerosis. What features dis- tinguish them? CASE HISTORIES IN RESPIRATORY MEDICINE 18 Answer 3d) There are two subsets of systemic sclerosis: limited cutaneous systemic sclerosis and d iffuse cutaneous systemic sclerosis. What features distin- guish them? See Table 3.2 . Table 3.2 Comparison of the two sub-types of systemic sclerosis Feature Form of cutaneous systemic sclerosis Limited (formerly called CREST syndrome) Diffuse Raynaud \200\231s phenomenon Present for years, and may be severe Occurs within one year of skin changes Skin changes Limited to hands, face, feet and forearms or absent. Late skin calcification and telangiect asia may occur Widespread skin involvement of both trunk and extremities Nails Dilated nail fold capillary loops Nail fold capillary dilatation and capillary destruction Pulmonary changes A significant late incidence of pulmonary hypertension with or without interstitial lung di sease Early and significant incidence of interstitial lung disease Other organ damage A significant late incidence of trigeminal neuralgia and liver disease Early and significant incidence of oliguric renal failure, diffuse gastrointestinal disease and myocardial infarction Antibodies A high incidence of anti- centromere antibody (70 \200\22380% of patients) Anti-Scl-70 (antitopoisomerase I) antibody positive (30% of patients). Presence associated with interstitial lung disease, and general disease activity CASE 3 19 Questions 3e) How should patients be monitored? 3f) Suggest treatment options. CASE HISTORIES IN RESPIRATORY MEDICINE 20 Answers 3e) How should patients be monitored? Patients with systemic sclerosis affecting the heart, lungs or kidneys require specialist a nd multi-disciplinary follow-up, and may need regular pulmo- nary function testing, echocar diography for estimation of pulmonary arterial pressures and renal function tests. Identifi cation of patients at risk is difficult, as the disease may be quiescent for long periods. The decision to start treatment is often difficult, as many patients have limited disease t hat may not progress. Factors prompting initiation of treatment are: \227\206 Deterioration in serial pulmonary function tests or CXR over the last 6 \200\22312 months \227\206 Severe respiratory disease (extensive disease on CT, moderate to severe reduction in TLCO or restrictive ventilatory defect) \227\206 Duration of systemic disease <5 years (especially <2 years) \227\206 Anti-Scl-70 (antitopoisomerase I) antibody positivity \227\206 Prominent ground glass attenuation on HRCT without traction bron- chial dilation or reticulation. 3f) Suggest treatment options. Most randomized clinical trials have been small ( n <40), and, due to the heterogenous natu re of systemic sclerosis, results are difficult to generalize. In view of this, treatment o f patients with severe disease is often based on expert opinion rather than randomized, con trolled trial data. Due to the equivocal clinical benefit, side-effects, cost, inconvenient routes of delivery of some drugs, therapy is often not given to those with mild disease. In interstitial lung disease, intra-venous or oral cyclophosphamide, and low-dose prednisol one are treatments of first choice. These tend to be con- tinued for one year, before conve rting to prednisolone and azathioprine. In pulmonary hypertension, a combination of calcium antagonists, sildenafil and an endothel in receptor antagonist (e.g. bosentan) are often used in combination. Referral of patients with pulmonary hypertension to a specialist center should be made. Calcium channel blockers, such as nifedipine, may be used to treat symptoms of Raynaud \200 \231s phenomenon, although they do not reverse skin changes, and may worsen oesophageal dys motility. An alternative option is topical glycerol trinitrate paste. CASE 3 21 The prostacyclin analogs, e.g. inhaled iloprost, oral beraprost and subcutaneous treprostin il, have been shown to have a beneficial effect on the vascular manifestations of systemic sclerosis, including both pulmo- nary hypertension (associated with significant improvement s in various pulmonary function, 6-minute walk test and dyspnoea index) and Raynaud \200 \231s phenomenon. Monthly dexamethasone injections may also have a modest beneficial effect on pulmonary function tests and frequency of Raynaud \200\231s attacks. Low-dose oral pred nisolone is sometimes used, although high doses tend to be avoided due to the possible risk of renal crisis, a rare complication of scleroderma, through an unknown mecha- nism. Other agents, such as methotrexate, azathioprine, interferons and antioxidants, have not been sh own to have a significant beneficial effect. Further reading Scleroderma lung disease Henness S and Wigley F ( 2007 ). Current drug therapy for scleroderma and secondary Raynaud \200\231s phenomenon: evidence-based review . Curr Opinion Rheum ; 19 : 611 \200 \223 618 . Highland K and Silver R ( 2005 ). New developments in scleroderma interstitial lung disease . Curr Opin Rheumatol ; 17 : 737 \200\223 745 . Latsi P and Wells A ( 2003 ). Evaluation and management of alveolitis and interstitial lung disease . Curr Opin Rheumatol ; 15 : 748 \200\223 755 . Tashkin D , Elashoff R , Clements P et al . ( 2006 ). Cyclophosphamide versus placebo in scleroderma lung disease . N Engl J Med ; 345 : 2655 \200\223 2666 . Supra-normal carbon monoxide transfer factor in restrictive lung disease Hart N , Cramer D , Ward S et al . ( 2002 ). Effect of pattern and severity of respiratory muscle weakness on carbon monoxide gas transfer and lung volumes . Eur Respir J ; 20 : 1 \200\223 7 . Case 4 A 42-year-old Caucasian female was referred with a cough. She had been diagnosed with asthm a 6 years previously on the basis of a recurrent cough, productive of clear or purulent spu tum, and exertional breathlessness; she had no history of wheeze and her peak flow values d id not vary significantly. She had been treated with high-dose inhaled corticosteroids and long acting beta-2 agonists with little benefit, and a course of oral prednisolone was unhelpful. A 3-month trial of p roton pump inhibitor therapy also gave no relief. She did intermittently use topical nasal steroids for sinusitis but had noticed no impact on her cough. She had never smoked. On examination her SaO 2 was 98% on air. She had crackles in both mid- zones on auscultatio n but no wheeze. Her pulmonary function tests are shown in Table 4.1 (NB Patient coughed du ring expiratory maneuvers). Table 4.1 Pulmonary function tests Measured % Predicted PEFR(L/min) 270 85 FEV1(L) 1.4 71 FVC (L) 2.3 75 FEV1/FVC ratio (%) 59 VA(L) 3.6 78 TLCO(mmol/min/kPa) 3.58 55 KCO(mmol/min/kPa/L) 1.01 71 No change following administration of 5mg nebulized salbutamol Her CXR was normal and a thoracic CT was arranged (basal slices, Fig. 4.1). CASE 4 23 Fig. 4.1 HRCT chest. Questions 4a) Describe the lung function test results. 4b) What do the CT images show? 4c) What investigations would you like to do next? CASE HISTORIES IN RESPIRATORY MEDICINE 24 Answers 4a) Describe the lung function test results.