Fig. 26.2 CT thorax. Questions 26e) Interpret the CT scan (Fig. 26.2). 26f) What diagnosis are the appearances most consistent with? CASE HISTORIES IN RESPIRATORY MEDICINE 210 Answers 26e) Interpret the CT scan (Fig. 26.2). The CT (Fig. 26.2) shows an enlarged heart, bilateral pleural effusions, bilateral ground g lass opacification in a predominantly central and upper zone distribution. There are areas of peripheral consolidation. There is also interlobar septal thickening ( Fig. 26.3 ), whic h is not irregular or nodular. The lymphadenopathy identified on the initial CT (not shown) had not changed significantly but the parenchymal changes were obscuring the previously id entified nodules and so it was not possible to comment on any interval changes to them. Interlobar septal thickening Fig. 26.3 Selected CT section. Interlobar septal thickening is commonly caused by fluid, where the thickening is smooth, o r malignant infiltration of lymphatics (lym- phangitis), where it is more nodular. It can a lso be a finding in interstitial fibrosis (irregular septal thickening) and rarely in bronc hiectasis. 26f) What diagnosis are the appearances most consistent with? Despite the previously normal echo, these appearances are most consistent with ongoing pulm onary oedema. The positive ANCA raised concerns of vasculitis, and hence pulmonary hemorrha ge should be considered. The CT appearances are not those of vasculitis or pulmonary haemor - rhage, and the lack of any change in hemoglobin would also go against pulmonary hemorrhag e. There is often wide inter-observer variation in the reporting of left ventricular systolic function (LVSF) on USS, but even if LVSF appears normal, diastolic dysfunction (especially in hypertensive patients) alone can cause clinically evident heart failure. CASE 26 211 Progress More aggressive diuretic treatment was commenced, which did improve the situation symptomat ically and radiologically. A repeat cardiac USS was performed, which was again reported as normal. Subsequently, renal artery stenosis (unilateral, left-sided) was demonstrated by MR angiography. The renal team advised that this would not have been a cause for his pulmonar y oedema, as it was unilateral and not an especially tight stenosis; therefore, no further intervention for this was recommended. In addition, a myocardial perfusion scan showed no e vidence of regional ischaemia. The precise cause of his pulmonary oedema remained unclear a nd the cardiologists did not recommend coronary angiography. Repeat C-ANCA titre remained 1 /40 with Anti-PR3 of 123U/mL and creatinine remained around 200 mol/L. The renal team suggested that diabetic nephropathy, and not renal vasculi- tis, was respons ible for the chronic renal impairment. A renal biopsy was not felt to be necessary at this point. At chest clinic review 2 months later he had a residual cough and reduced exercise toleranc e with dyspnoea at 200 yards. Clinical examination revealed no evidence of cardiac decompen sation and a clear chest. CASE HISTORIES IN RESPIRATORY MEDICINE 212 Fig. 26.4 CXR at chest clinic review. CASE 26 213 Fig. 26.5 Interval CT thorax. Questions 26g) Interpret the CXR (Fig. 26.4) and CT (Fig. 26.5). 26h) What is the next investigation? CASE HISTORIES IN RESPIRATORY MEDICINE 214 Answers 26g) Interpret the CXR (Fig. 26.4) and CT (Fig. 26.5). The most striking abnormality shown on the CXR (Fig. 26.4) and the CT (Fig. 26.5) is the de velopment of a fairly rounded opacity in the left- upper zone, which may be pleurally based . There is also some persisting atelectasis in the right-lower zone. Although the heart app ears enlarged, there does not appear to be any persisting pulmonary oedema. The CT (Fig. 26.5) also shows bilateral spiculated nodules of varying size, with evidence o f cavitation in the right-lower lobe nodule. In addition, there is an area of consolidation anteriorly in the RLL. There is right par- atracheal lymphadenopathy. 26h) What is the next investigation? Core biopsy of left-upper lobe lesion would be the best next investigation, although a nasa l mucosal biopsy might have helped. The differential diagnosis is of Wegener \200\231s granulomatosis, organizing pneumonia and multi-focal intra-thoracic malignancy (including lym- phoma). Eosinophilc pneumonia should be considered, but would be discounted by lack of peripheral eosinophilia. Core biopsy of the lung lesion is, therefore, required to differentiate these. Although the right paratrac heal node would be amenable to tansbronchial needle aspiration, the only diagnosis this cou ld realistically secure would be of carcinoma. Core biopsy was performed. Tissue obtained showed patchy chronic inflammation including epi thelioid macrophages. No well formed gran- ulomas were seen nor tissue necrosis. No vasculi tis was observed. CASE 26 215 Questions 26i) What final investigation is required? 26j) What is your diagnosis? 26k) What drug treatment would you commence? CASE HISTORIES IN RESPIRATORY MEDICINE 216 Answers 26i) What final investigation is required? Renal biopsy. This is required to determine therapeut ic strategy (see below). Histology of this showed no evidence of renal vasculitis, but esta blished diabetic nephropathy only. 26j) What is your diagnosis? Non-renal Wegener \200\231s granulomatosis. Despite the lung biopsy not con- firming pathol ogically evident vasculitis, results so far are in keeping with a systemic vasculitis invol ving the upper (nasal symptoms initially described) and lower respiratory tract. 26k) What drug treatment would you commence? The management will be in two phases, namely induction and mainte- nance of remission. Prev ious conventional treatment of ANCA-associated systemic vasculitis would be combined cyclop hosphamide and high- dose prednisolone for induction, with cyclophosphamide continued for a t least one year and prednisolone gradually tapered over this time. This leads to remission in about 90% of cases. Concern regarding toxicity of cyclophosphamide (bone-marrow toxicit y, infection, myeloproliferative diseases) has led to recent studies addressing alternative , potentially less toxic treatment regimens. Recent evidence has suggested that in patients with systemic ANCA- associated vasculitis (W egener \200\231s or microscopic polyangiitis), but with- out life-threatening features (inc luding severe haemoptysis with bilateral infiltrates) or significantly impaired renal funct ion (creatinine >150 mol/L), induction of remission can just as effectively be achieved wi th methotrexate (MTX) as with cyclophosphamide (CYC) (de Groot et al . 2005). In this study , patients received either 15mg/week MTX ( n = 49) increasing to maximum 20 \200\22325mg/we ek by 12 weeks for a total of 12 months, or 2mg/kg/day CYC ( n =46) for 3 \200\2236 months. At remission, CYC was reduced to 1.5mg/kg/day until month 10, when it was tapered and stop ped by 12 months. Both groups received prednisolone 1mg/kg/ day for 12 weeks, then tapered to 15mg/day at 12 weeks, 7.5mg/day at 6 months and stopped at 12 months. Most (89) had Wege ner \200\231s and about half in each arm had lung involvement. At 6 months, the remission r ate in the MTX group (44/49, 89.8%) was not statistically significantly less than the rate in the CYC group (43/46, 93.5%). Time to remission with MTX was longer in the subgroup with respiratory tract involvement (nodules and/or cavities and/or pulmonary infiltrates). Rela pse rates at CASE 26 217 18 months of 69.5 and 46.5% in MTX and CYC groups, respectively, suggests treatment should be continued beyond 12 months. A further study (Jayne et al . 2003) comparing maintenance therapy with azathioprine ( n =7 6), versus cyclophosphamide ( n =79), following induction with prednisolone and cyclophosph amide, found no signifi- cant difference in relapse rates between the two treatment arms. T his study included patients with life-threatening features at presentation, and approximate ly half in each arm had lung involvement. There are no studies comparing induction and/or m aintenance regimens specifically in patients with lung involvement by systemic vasculitis. The majority (75 \200\22390%) of patients with active Wegener \200\231s granulomatosis have p-ANCA/PR3-ANCA, and around 20% have p-ANCA/MPO-ANCA. The specificity of ANCA testing for Wegener \200\231s depends on laboratory methods used, and reaches 99% if target-antigen-spe cific test methods are used in combination with immunofluoresence. Further reading De Groot K , Rasmussen N , Bacon PA, Tervaert JW, Feighery C, Gregorini G et al . ( 2005 ). Randomized trial of cyclophosphamide versus methotrexate for induction of remission in earl y systemic antineutrophil cytoplasmic antibody associated vasculitis . Arthritis and Rheuma tism ; 52 ( 8 ): 2461 \200\223 4269 . Jayne D , Rasmussen N , Andrassy K, Bacon P, Tervaert JW, Dadonien J, et al . ( 2003 ). A randomized trial of maintenance therapy for vasulitis associated with antineutrophil cytop lasmic antibodies . NEJM ; 349 : 36 \200\223 44 . Langford CA , Specks U ( 2003 ). Wegener \200\231s granulomatosis and other vasculitides . In Gibson GJ , Geddes DM , Costabel U et al . (eds) Respiratory Medicine ( 3 rd edn). Saund ers , London , chapter 57 . This page intentionally left blank Case 27 Three case histories are described in brief below. Case A A 60-year-old man with known sero-positive rheumatoid arthritis, controlled with weekly met hotrexate and non-steroidal anti-inflammatory medication, presented with a left-sided pleur al effusion discovered incidentally on a CXR prior to an inguinal hernia repair. He had no respiratory symptoms. Thoracic CT confirmed presence of a pleural effusion but no other abn ormality, with normal appearing pleural surfaces. Pleural aspiration yielded slightly cloud y fluid, analysis of which is documented in Table 27.1 and illustrated in Fig. 27.1 . (a) (b) Fig. 27.1 (a) Giemsa staining and (b) birefringence of pleural fluid from patient A, demons trating birefringent rhomboidal cholesterol crystals (courtesy of Dr Colin Clelland). Case B A 34-year-old woman developed sudden onset of left-sided posterior pleuritic chest pain and dyspnoea whilst stretching during yoga exercises; she was unable to continue due to pain. On examination, she was well but in obvious discomfort and had reduced air entry at her lef t lung base. A CXR showed small bilateral pleural effusions. These were confirmed on a CT c hest, and CT pulmonary angiogram, which demonstrated no thrombo-embolic disease, lymphadeno pathy or pleural abnormality. Left pleural aspiration yielded milky-colored fluid ( Fig. 27 .2 ). Results of pleural fluid analysis are shown in Table 27.1 . Her pain eased spontaneou sly within 24h and on review at 6 months she remained well. CASE HISTORIES IN RESPIRATORY MEDICINE 220 Fig. 27.2 Aspirated pleural fluid from patient B. Case C A 76-year-old ex-smoker (40-pack years) presented with 3 months of progres- sive exertional dyspnoea, anorexia with two-stone weight loss and right-sided sub-scapular pain. A CXR con firmed examination findings of a moderate pleural effusion. Pleural aspiration revealed clo udy blood-stained fluid (pleu- ral fluid results in Table 27.1 ) and subsequent CT imaging showed extensive lymphadenopathy (supra-clavicular, mediastinal, paratracheal, axillary, re tro- peritoneal and mesenteric) and a moderate pleural effusion with minimal pleural enhanc ement. Investigations Table 27.1 Pleural fluid results Patient A Patient B Patient C Protein (>35g/L represents an exudate, and <25g/L a transudate) 50 41 42 Lactate dehydrogenase, (normal range 110 \200\223250IU/L) 1694 156 151 Glucose (mmol/L) 1.0 6.4 6.9 Cholesterol (mmol/L) 5.7 6.7 3.1 Triglyceride (mmol/L) 0.15 32.3 10.78 Chylomicrons Absent Present Present Cholesterol crystals Present (see Fig. 27.1) Absent Absent CASE 27 221 Questions 27a) What is the diagnosis, based on the pleural fluid analysis in each case? 27b) How could the pleural fluid aid differentiation between these diag- noses and empyema? 27c) What two conditions are commonly associated with the diagnosis in patient A? What is the prognosis? 27d) How would you investigate patient A to confirm your diagnosis? CASE HISTORIES IN RESPIRATORY MEDICINE 222 Answers 27a) What is the diagnosis, based on the pleural fluid analysis in each case? The pleural fluid analyzes confirm patient A has a pseudochylothorax. Detection of cholesterol crystals is diagnostic of a pseudochylothorax (chyliform effusion or \200\230cholesterol pleurisy \200\231). However, their absence does not exclude the dia gnosis. A pleural fluid cholesterol level >5.2 mmol/L (200mg/dL) is usually seen, chylomicr ons are always absent. Pseudochylothorax usually arises from a long-standing ( \211 5 years) pleural effusion. It is likely that lysis of cells within the pleural space releases cholesterol and lecithin \200\223globulin complexes, which are poorly absorbed across the thickened pleural membrane . Patients B and C each have a true chylothorax. Diagnosis of a true chylothorax requires t he presence of chylomicrons on lipoprotein electrophoresis, or a triglyceride concentration >1.24mmol/L (110mg/dL). A chylothorax develops when there is disruption of the thoracic duct, or one of its tributa ries, resulting in passage of chyle (lymph rich in chy- lomicrons, the macromolecules that transportation fat from the intestine to the liver and adipose tissue) into the pleural spa ce. \227\206 The thoracic duct originates anterior to the L2 vertebra and enters the posterior mediastinum through the aortic hiatus of the diaphragm. It ascends through the thorax roug hly in the mid-line, between the descending aorta on the left and the azygos vein on the ri ght, until the level of the T5 vertebra. It then crosses to the left behind the oesopha- gu s and continues upwards between the left side of the esophagus and the left pleura, in the left posterior mediastinum, to above the 1st rib. After exiting the thorax it forms an arch at the level of vertebra C7, behind the jugular vein, and turns laterally and downward to empty into the venous circulation at the angle of the junction of the left jugular and subc lavian veins. \227\206 Significant anatomical variations exist. \227\206 Injury or obstruction below where the duct traverses vertebra T5 usu- ally result s in a right-sided chylothorax, whereas disease above this point lead to a left-sided chylo thorax. Cervical thoracic duct rupture may result in bilateral chylothoraces. CASE 27 223 27b) How could the pleural fluid aid differentiation between these diag- noses and empyema? The supernatant of pleural fluid from a chylothorax typically fails to clear after centrifu gation, unlike with an empyema when sediment col- lects leaving a clear supernatant. 27c) What two conditions are commonly associated with the diagnosis in patient A? What is the prognosis? The most common causes of pseudochylothoraces are: (1) tuberculous pleurisy and (2) rheumat oid pleuritis. Trauma, lung cancer, pleuro- pulmonary paragonimiasis and hepato-pulmonary e chinococcosis may rarely cause pseudochylothoraces. The prognosis of pseudochylothorax is usually good, although clearly depends on the underly ing cause. Therapeutic thoracentesis may relieve dyspnoea but pleural fibrosis may limit sy mptomatic improvement and, in a minority of patients, decortication is considered. Respirat ory insuffi- ciency, pleural infection and fistulae (bronchopleural or pleurocutaneous) are rare complications. 27d) How would you investigate patient A to confirm your diagnosis? Ziehl \200\223Nielsen staining of pleural fluid and culture for acid-fast bacilli should be requested and pleural biopsies considered to exclude caseating granulomatous infiltrate. A negative interferon gamma release assay (e.g. Elispot) would effectively exclude underlyin g tuberculosis making it safe to assume this case is due to rheumatoid arthritis. Questions 27e) What are the likely underlying causes in patients B and C? What is their prognosis? 27f) What other underlying conditions are associated with this diagnosis? 27g) What treatments should be considered for each patient? CASE HISTORIES IN RESPIRATORY MEDICINE 224 Answers 27e) What are the likely underlying causes in patients B and C? What is their prognosis? Patient B. Thoracic duct rupture has been described related to physical st retching and movement, which is a possible cause of the bilateral chylothoraces in this cas e. Formation of a localized chyle collection ( \200\230chyloma \200\231) reflects initial d uct leakage and can precipitate acute chest pain and dyspnoea. \200\230Spontaneous \200\231 bilateral chylothoraces have been described for which no unde rlying cause is identified. Patient C. The CT appearances suggested thoracic duct obstruction by malignant external lym ph node compression, the most common cause for which is lymphoma. Subsequent axillary lymph node biopsy demon- strated infiltration with neoplastic follicles consistent with underlyi ng follicular cell lymphoma. The prognosis of chylothorax varies dependent on the underlying cause. Malignant chylothora x, chronic debilitating chylothoraces and bilateral disease carry a worse prognosis. Prompt intervention to minimize chyle loss and maximize nutritional support have improved outcome . 27f) What other underlying conditions are associated with this diagnosis? Causes of true chylothorax may be classified as: \227\206 Traumatic. Thoracic duct trauma accounts for approximately 50% of cases. Iatrogen ic cases frequently arise secondary to damage during car- diothoracic surgery, i.e. aortic coarctation repair or oesophagectomy, and are a significant cause of post-operative morbidi ty and mortality. Other iatrogenic causes, such as central venous catheterization or pace- maker insertion, are occasionally implicated. Non-iatrogenic trau- matic precipitants inclu de blunt chest trauma (e.g. seat-belt injuries) or penetrating injury. \227\206 Malignant. Malignancy, particularly lymphoma (70% of malignant cases), can cause thoracic duct disruption. \227\206 Congenital. Congenital chylothorax arises from thoracic duct malfor- mation or at resia. Birth trauma and repair of diaphragmatic defects may precipitate a chylothorax. \227\206 Miscellaneous. Lymphangioleiomyomatosis (LAM) (see case 9) is a rare cause; in on e series, 10% of patients with LAM had a chylothorax over a 25-year period. Idiopathic chylothoraces occur in 6 \200\22315%. Spontaneous bilateral chylot- horaces have been described. CASE 27 225 27g) What treatments should be considered for each patient? Patient A. As the patient is asymptomatic, if TB is excluded, no treat- ment is required. Patient B. Traumatic rupture of the thoracic duct often heals spontane- ously. Given patien t B \200\231s clinical improvement and lack of symptoms no intervention is required. Patient C. Treatment of malignant chylothorax should be directed at the underlying primary cancer. Resolution of the chylothorax occurs in almost 70% of patients with lymphoma follow ing radiotherapy and chemotherapy. This patient should be referred to the haem-oncology tea m for appropriate management of her lymphoma. Persistent symptoms, despite systemic therapy, warrant specific treat- ment of the effusion with pleural drainage, and talc pleurodesis if full lung re-expansion occurs. Pleuro-perit oneal or pleuro-venous shunting has been used in patients with no chyloascites and recycles the nutri- tional component of the extravasated chyle. Management decisions for patients with chylothorax depend upon the etiology with no randomi zed trial data existing to guide therapy. The universal approach should aim to: (i) optimiz e nutrition, (ii) relieve symp- toms and (iii) close the thoracic duct defect. Identificati on of the leakage point during operative repair is achieved by giving the patient either a lipophilic dye or high fat content fluid, e.g. cream, orally beforehand. \227\206 Post-operative chylothoraces are associated with a mortality of approx- imately 5 0%. A conservative approach with chest tube drainage and TPN may work, especially in those patients with low initial rates of fluid drainage. Immunocompromised or malnourished patien ts, and those draining large volumes of chyle, may benefit from early surgical intervention as the defect rarely closes spontaneously. \227\206 Idiopathic chylothorax. Therapeutic thoracentesis and adoption of a low-fat diet with medium-chain triglycerides (MCT) may be adopted in an attempt to reduce chyle flow. Th is is often of limited success, as the diet is often unpalatable and does not reduce chyle flow as effec- tively as a fasting state and total parenteral nutrition (TPN). However, res olution occurs in up to 80% of compliant patients. \227\206 Other strategies include: Octreotide, a somatostatin analog, has been reported in pediatric series to enhance thoraci c duct closure and reduce chyle production. The exact mechanism of action remains unclear; it probably includes reduction of intestinal fat absorption (mainly triglycerides), an CASE HISTORIES IN RESPIRATORY MEDICINE 226 increase in fecal fat excretion, and a possible attenuating effect on thoracic duct lymph f low. Image-guided percutaneous thoracic duct embolization may be attempted before surgical thora cic duct ligation is considered. This offers a minimally invasive treatment for patients un fit for surgery. VATS or thoracotomy allows ligation, over-sewing or fibrin glue application to try and achi eve surgical closure of a thoracic duct defect. Case 28 A previously fit and well 23-year-old banker was admitted on the acute medi- cal take with an 8-week history of progressive exertional breathlessness, worse over the preceding 3 days . He also reported a brief episode of central pleuritic chest pain on the day of admission. On admission his oxygen saturation was 91% at rest on air. His pulse was 100bpm and BP 101/ 59. His JVP was visible (+3cm). His calves were soft and non-tender and his chest clear. Investigations \227\206 Full blood count, U&E and liver function were within normal limits \227\206 INR 1.3, troponin I 0.8 \227\206 ABG on air, pH 7.4, PaCO 2 3.0kPa, PaO 2 7.8kPa , [HCO 3 ] 24.5mmol/L, BE \200\2230.95mmol/L \227\206 ECG, sinus tachycardia 110bpm with anterior T wave inversion \227\206 His CXR and CT pulmonary angiogram are shown in Fig. 28.1 . CASE HISTORIES IN RESPIRATORY MEDICINE 228 (a) Fig. 28.1 (a) CXR CASE 28 229 (b) Fig. 28.1 (b) CT pulmonary angiogram. Questions 28a) What does the CXR show ( Fig. 28.1a )? 28b) What is the diagnosis? CASE HISTORIES IN RESPIRATORY MEDICINE 230 Answers 28a) What does the CXR show ( Fig. 28.1a )? There is mild cardiomegaly with either upper lobe blood vessel pre- dominance, or lower zon e oligaemia. His right costophrenic angle is blunted. 28b) What is the diagnosis? Extensive bilateral pulmonary emboli are demonstrated on the CT pul- monary angiogram. The right lower and middle lobe pulmonary arteries were completely occluded. There was also evi dence of right ventricular strain, i.e. RV (right ventricle, measured at the level of the t ricuspid valve) to LV (left ventricle, measured at the level of the mitral valve) diameter ratio >1 (see Fig. 28.2 ). An RV to LV diameter ratio >1 is also suggestive of severe PE an d associated with a more than three-fold increase in risk of intensive care admission (Arao z et al . 2003), and death. Evidence of RV strain on CTPA has a sensitivity of approximatel y 78 \200\22392% and specificity of 100% for the presence of RV dysfunction, when compared to echocardiographic findings (Ghaye et al . 2006). CASE 28 231 Fig. 28.2 CT pulmonary angiogram. RV 4.6cm: LV 4.2cm, ratio >1 (arrows denote site of measu rement for calculation of the RV:LV ratio). Progress The patient was admitted to the ward and started on a therapeutic dose of low molecular wei ght heparin and warfarin treatment. However, on day two he became more breathless. On examination he was anxious and oxygen-dependent with Sa O 2 on 100% oxygen of 97% (86% o n air). He had a persisting tachycardia, >115bpm, BP 120/70 and tachypnoea (>25 per minute) . Investigations \227\206 ABG on 100% oxygen, pH 7.45, PaCO 2 4.7kPa, PaO 2 14.7kPa. \227\206 Trans-thorac ic echocardiography: normal left ventricular function, dyskinetic septum, and a dilated rig ht ventricle with mild-moderately impaired function. The aortic valve was bicuspid, with ro ot dilatation, and the estimated pulmonary artery pressure was 30mmHg (includ- ing the CVP in mmHg). \227\206 Doppler ultrasound of both legs showed no evidence of proximal DVT. Questions 28c) Should the results of these tests alter your management? 28d) How and when would you assess risk for future thrombo-embolic events? 28e) Is thrombolysis indicated? CASE HISTORIES IN RESPIRATORY MEDICINE 232 Answers 28c) Should the results of these tests alter your management? No. This patient has had a sub-massive PE with evidence of right ven- tricular dysfunction on echocardiography. Treatment with anticoagula- tion is appropriate \200\224therapeutic do se low molecular weight heparin should be administered initially and oral anticoagulation ( usually warfa- rin) commenced at the same time. Heparin should be continued for at least 5 days (the time needed to ensure reduction in the vitamin K-dependent clotting factors affec ted by warfarin) and then discontin- ued once the international normalized ratio (INR) has been >2 for 48h. Echocardiographic findings aid prognostication for patients with PE but do not form part of the routine acute assessment. However, RV hypokinesia is present in 40% of those with a sy stolic blood pressure >90mmHg and impaired RV function is an independent predictor of morta lity at 90 days. Persistent pulmonary hypertension (after 6 weeks), a patent foramen ovale (>4mm) and mobile right-heart thrombus are all recognized markers of a poor prognosis. Raised troponin concentrations indicate myocardial injury and indicate a group at higher ri sk of death. In one study, elevation of troponin I >1.5ng was associated with RV dysfunctio n and increased mortality rates. Other potential prognostic markers in PE include: \227\206 Brain natriuretic peptide (BNP) \200\224levels are higher in those with PE, par- ticularly with RV impairment, and may be predictive of adverse outcome. \227\206 Heart-type fatty acid binding protein (H-FABP) has been mooted as a promising ear ly marker of RV damage in acute PE (Puls et al . 2007). 28d) How and when would you assess risk for future thrombo-embolic events? There is currently no consensus concerning who to screen for throm- bophilia disorders foll owing venous thrombo-embolism (VTE). An individual approach should be taken, with routine s creening for occult malignancy not recommended. However, testicular examination in a young male with VTE, prostate specific antigen (PSA) measurement in older men and a breast examin ation in female patient are prudent. Screening would be appropriate for patients: \227\206 Age <50y with spontaneous VTE \227\206 With recurrent thrombosis \227\206 With a family history of VTE \227\206 With VTE in association with pregnancy or use of oral contraceptive \227\206 Unusual site of VTE (e.g. sagittal sinus, axillary, mesenteric, portal) \227\206 With history of warfarin induced skin necrosis. CASE 28 233 Testing should be performed at least 2 weeks, and preferably one month, after completing an ticoagulation because: \227\206 Antithrombin concentrations, and occasionally protein C and S levels, can be reduced in acute thrombosis \227\206 Antithrombin levels can be reduced by heparin use \227\206 Warfarin reduces functional activity of protein C and S, and can falsely raise antithrombin levels However, factor V Leiden, prothrombin gene mutations and the presence of antiphospholipid a ntibodies can be screened for at any time. 28e) Is thrombolysis indicated? The use of thrombolysis in submassive PE is controversial. At present the only indication f or use of thrombolytic therapy in PE is a clinically massive event with haemodynamic instab ility (systolic BP <90mmHg, or a fall of 40mmHg for 15 minutes not due to other causes). So me clinicians consider refractory hypotension or hypoxaemia, and right ventricular dysfunct ion appropriate indications for thrombolysis (Konstantinides et al . 2002); how- ever, nati onal guidelines do not support its use in these settings. Progress On day 3, despite continuous high-flow oxygen, the patient became increas- ingly agitated a nd distressed. CPAP was commenced on the High Dependency Unit and oxygen saturations mainta ined around 90% with 7cmH 2 0 and inspired oxygen concentrations of 85%. Investigations \227\206 HR 134, BP 110/65 \227\206 ABG on CPAP 7cmH 2 0, FiO 2 0.85: pH 7.50, PaCO 2 4.3 kPa, PaO 2 8.84kPa, SaO 2 91%, [HCO 3 ] 24.3mmol/L, BE \200\2231.6mmol/L \227\206 INR 2.0 \227\206 CXR no new changes. Questions 28f) Discuss the pros and cons of the following treatment options: \227\206 Discuss with cardiothoracic surgeons possible embolectomy \227\206 Proceed to endotracheal intubation \227\206 Perform medical thrombolysis \227\206 Insert an inferior vena caval (IVC) filter. CASE HISTORIES IN RESPIRATORY MEDICINE 234 Answer 28f) Discuss the pros and cons of the following treatment options: \227\206 Discuss with cardiothoracic surgeons possible embolectomy \227\206 Proceed to endotracheal intubation \227\206 Perform medical thrombolysis \227\206 Insert an inferior vena caval (IVC) filter. \227\206 Surgical embolectomy, catheter embolectomy or clot fragmentation is neither widel y available nor recommended in submassive PE. However, in massive PE, if thrombolysis is co ntraindicated or haemodynamic instability persists, the case should be discussed with the l ocal cardiot- horacic team. There are no randomized controlled trials comparing efficacy of surgical intervention versus thrombolytic therapy in sub- massive PE. \227\206 Full resuscitation should be performed in all patients with full intensive care s upport, including invasive ventilation and inotropes, if required. \227\206 There is no evidence to suggest improvement of clinical outcome with the addition of thrombolytic therapy to standard treatment in patients with submassive PE. However, in patients with massive PE i.e. with signs of haemodynamic instability, without absolute cont raindication, thrombolysis should be administered. \227\206 In non-massive PE, IVC filter placement reduces the rate of recur- rence, but has no impact on overall mortality, and increases the inci- dence of subsequent deep vein thro mbosis. Insertion should be considered for patients with massive PE when potential addition al emboli might be catastrophic. Progress The cardiothoracic surgical team did not recommend surgical embolectomy and thrombolysis wa s performed with rt-PA. An immediate improvement with reduced oxygen demand (PaO 2 34kPa on 60% oxygen) and resolution of dys- pnoea was seen. However, a few hours later he suddenly deteriorated and became unresponsive following a witnessed grand mal seizure. On examina- t ion he had evidence of a left hemisphere stroke. CASE 28 235 Question 28g) What do you think has happened? CASE HISTORIES IN RESPIRATORY MEDICINE 236 Answer 28g) What do you think has happened? He could either have suffered a cerebral hemorrhage secondary to the thrombolysis, or had a cerebral infarction as a result of paradoxical emboli through a pre-existing intra-cardiac shunt, e.g. patent foramen ovale (PFO) or atrial septal defect (ASD). Progress He was intubated and ventilated. A CT brain showed left-middle cerebral artery infarction w ith oedema and resultant mid-line shift. A trans-oesophageal echocardiogram showed reductio n in the PAP (40mmHg) but revealed a patent foramen ovale. Further neurological decline occ urred and following discussion with the patient \200\231s family active treatments were sto pped. Conclusion This case demonstrates a delayed paradoxical embolism through a patent PFO in a young man w ho received thrombolysis for a PE. A PFO is present in up to 26% of people on autopsy and i s often associated with a poor prognosis and higher mortality in patients with PE. As a con sequence of raised right-sided heart pressures, due to the PE, the PFO would have opened al lowing right-to- left intra-cardiac shunting (increasing an already elevated A-a gradient) and paradoxical embolization of the thrombus resulting in the catastrophic out- come seen h ere. The role of thrombolysis in non-massive PE remains controversial. Current guidelines do not recommend its use. Further reading Araoz PA , Gotway MB , Trowbridge RL , Bailey RA , Auerbach AD , Reddy GP ( 2003 ). Helical CT pulmonary angiography predictors of in-hospital morbidity and mortality in patients with acute pulmonary embolism . J Thorac Imaging ; 18 : 207 \200\223 216 . Dong BR , Yue J , Liu GJ , Wang Q , Wu T ( 2006 ). Thrombolytic therapy for pulmonary embolism . Cochrane Database of Systematic Reviews ; 2 : CD004437 . Ghaye B , Ghuysen A , Bruyere PJ , D Orio V , Dondelinger RF ( 2006 ). Can CT pulmonary ang iography allow assessment of severity and prognosis in patients presenting with pulmonary e mbolism? What the radiologist needs to know . Radiographics ; 26 : 23 \200\223 39 . Konsta ntinides S ( 2002 ). The case for thrombolysis in acute major pulmonary embolism: hemodynamic benefits and beyond . Intensive Care Med ; 28 : 1547 \200\223 1551 . Puls M , Dellas C , Lankeit M , Olschewski M , Binder L , Geibel A ( 2007 ). Heart-type fat ty acid-binding protein permits early risk stratification of pulmonary embolism . Eur Heart J ; 28 : 224 \200\223 229 . Tapson VF ( 2008 ). Acute pulmonary embolism . N Engl.J Med ; 358 : 1037 \200\223 1052. Case 29 A 17-year-old adolescent was referred for optimization of exercise-induced asthma control. His complaints were of exercise-induced dyspnoea, cough, wheeze and choking episodes during competitive sport, particularly rugby. On three occasions his symptoms were so severe that an ambulance was called. The patient reported that the crew had said he was very wheezy an d oxygen relieved his symptoms, but he was not admitted to hospital. Symptoms were unreliev ed by inhaled salbutamol taken before and after exercise. He had no nocturnal symp- toms, a nd other daytime activities were not restricted. He had been diagnosed with asthma by his G P 6 months previously, and at the time of review was taking combined salmeterol and flutica sone at a dose of 250 g fluticasone, two puffs twice daily. This had failed to control his symptoms. Examination was normal. Investigations \227\206 Hb 13.2 \227 10 9 /L, WCC 8.4 \227 10 9 /L (eosinophils 0.25 \227 10 9 /L), pl ate- lets 365 \227 10 9 /L \227\206 Total IgE 47kU/L, precipitating serum IgG antibodies to Aspergillus fumigatus negative, Aspergillus -specific IgE < 0.35KU/L \227\206 Peak flow in clinic 520L/m (90% predicted), serial peak flow chart kept for prece ding 3 weeks showed no evidence of diurnal variability. CXR normal. \227\206 Pulmonary function is shown in Table 29.1. Table 29.1 Pulmonary function tests Measured % Predicted FEV1(L) 4.1 108 FVC(L) 5.0 116 FEV1/FVC 82 RV(L) 1.6 138 TLC(L) 6.7 116 VA(L) 6.2 121 TLCO(mmol/min/kPa) 12.64 117 KCO(mmol/min/kPa/L) 2.04 97 Questions 29a) What features are in favor or against the diagnosis of exercise- induced asthma? 29b) What would be the most appropriate next investigation? CASE HISTORIES IN RESPIRATORY MEDICINE 238 Answers 29a) What features are in favor or against the diagnosis of exercise- induced asthma? The diagnosis of exercise-induced asthma cannot be made with certainty at present, primaril y given the lack of improved symptoms with a short- acting bronchodilator. Exercise-induced asthma can be present in the absence of asthma symptoms at other times. The absence of obj ective measures of poor (conventional) asthma control (lack of PEFR variability, or demonst rable airflow obstruction) does not exclude exercise-induced asthma. The patient has been t aking a moderate dose of inhaled corticos- teroid (ICS) with a long-acting bronchodilator. ICS usually reduce the severity of exercise-induced asthma symptoms, but these can still oc cur, even when there is adequate control of daytime symptoms and normal resting measures of airway caliber. Salmeterol gives good protection against exercise-induced asthma, but its long onset of action requires it to be taken at least 30 minutes (optimally 2.5h) before ex ercise. Also, regular use of salmeterol as a preventative measure for exercise-induced asth ma is associated with development of tolerance to its protective effect. From the data pres ented, the only objective support for exercise-induced asthma is the isolated finding of ai r-trapping (RV 138% predicted, versus TLC 116% predicted) suggesting possible mild chronic airflow limitation. 29b) What would be the most appropriate next investigation? Exercise testing with lung function would be the most appropriate next investigation. The t ype of exercise testing will vary depending on local availability, but it is important that the intensity of exercise in the labora- tory mirrors that in the field, and standardized conditions are recom- mended (e.g. FEV 1 measurement pre-exercise and 1, 3, 5, 7, 10, 15 an d 20 minutes post-exercise). Other measures of airway inflammation, such as sputum eosinoph il quantification or a methacholine challenge, are unlikely to be helpful in clarifying the nature of the exercise induced symptoms. Progress Exercise testing was performed, which recreated his symptoms. Post-exercise spirometry and flow-volume loop are shown in Table 29.2 . CASE 29 239 Table 29.2 Minutes post-exercise FEV1 (L) PEFR (L/min) 0 3.9 510 1 3.8 510 2 3.75 490 3 3.7 500 5 3.8 490 8 3.7 500 20 3.8 480 Fig. 29.1 Flow volume loop showing three breaths at peak exercise. Expiration upwards, insp iration downwards, TLC far left of graph. Darker line is approximate predicted normal expir atory curve. Questions 29c) Interpret the exercise lung function data. 29d) What is the diagnosis? 29e) What management steps would you institute? CASE HISTORIES IN RESPIRATORY MEDICINE 240 Answers 29c) Interpret the exercise lung function data. The exercise spirometry shows no significant drop in either FEV 1 or PEFR to support the di agnosis of exercise-induced asthma. A fall of > 10% is considered abnormal and is used as a cut-off for diagnosis of exercise-induced asthma. The flow volume loop demonstrates severe truncation of the inspiratory limb with normal app earances of the expiratory limb, suggesting extra- thoracic upper airways obstruction, most likely from the glottis. 29d) What is the diagnosis? Exercise-induced vocal cord dysfunction. In vocal cord dysfunction (VCD) there is abnormal movement of the vocal cords during respira- tion (usually, but not uniformly, in inspiratio n) causing a number of symptoms, most commonly dyspnoea, stridor (which was the \200\230wh eeze \200\231 described by our patient), choking, throat tightness and cough.