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. The pathophysiology is unclear but probably involves interaction between laryngeal hyper-re sponsiveness, possible inflammatory insults or emotional triggers, and autonomic imbalance leading to symptoms. VCD has been described in association with exercise and in elite athle tes where diagnosis may require specific testing with the particular sporting activity, rat her than in the lung function lab. The gold standard for diag- nosis is visualization by la ryngoscopy of abnormal adduction of the anterior two-thirds of the vocal cords with the cre ation of a posterior glottic \200\230chink \200\231. This is usually needed during symptom s, as the cords are frequently normal between attacks. Asthma and psychiatric morbidity are frequent associations of VCD. In one of the largest series of VCD patients, asthma was pre sent in over 50% and 73% had a major psychi- atric disorder. On further questioning it was clear there was a significant psychological burden on this patient, with the death of his h alf- brother 6 months previously, stress from pending school exams and caring for his secon d disabled brother. 29e) What management steps would you institute? There are no randomized, controlled trials of treatment for VCD. Most case series of VCD de scribe the beneficial effect of speech therapy, but other forms of breathing retraining, su ch as can be delivered by a respi- ratory physiotherapist, may be of value. Psychological a ssessment may be helpful. Withdrawal of medication for previously presumed diag- noses (esp ecially asthma) is important if these are excluded. In the acute CASE 29 241 setting, success has been reported with Heliox (21% O 2 , 79% helium); this response may he lp in diagnosis also, given that reduction in airflow resistance would only be expected at sites of turbulent flow such as across a narrow laryngeal chink. Further reading Anderson S , Brannan J ( 2001 ). Exercise induced asthma . In: O \200\231Byrne PM and Thoms on NC (eds). Manual of Asthma Management ( 2nd edn). Saunders , London , chapter 36 , pp. 471 \200\223 486 . Ayers J , Gabbott PL ( 2002 ). Vocal cord dysfunction and laryngeal hyperresponsiveness: a function of altered autonomic balance? Thorax ; 57 : 284 \200\223 285 . McFadden ER Jr , Zawadski DK ( 1996 ). Vocal cord dysfunction masquerading as exercise- ind uced asthma. a physiologic cause for \200\230choking \200\231 during athletic activities . AJRCCM ; 153 : 942 \200\223 947 . Newman KB , Mason UG , Schmaling KB ( 1995 ). Clinical features of vocal cord dysfunction . AJRCCM ; 152 : 1382 \200\223 1386 . This page intentionally left blank Case 30 A 29-year-old lawyer, 16 weeks pregnant, presented with cough, wheeze and dyspnoea on exert ion; she had also required antibiotics for repeated chest infections and lost 15kg in weigh t since her previous pregnancy 2 years previ- ously. At that time she had been diagnosed wi th asthma when she also had shortness of breath. This had responded well to salbutamol and beclometha- sone and, in retrospect, there had been previous episodes of self-limiting coug h and wheeze over several years. She had had a normal CXR a year previously. There were no pets at home and she was taking c ombined salmeterol and flixotide via a spacer. She had not had any oral steroids recently. On examination she was pale and tachycardic. There were crackles and wheezes throughout the chest. Investigations \227\206 SaO 2 , 98% \227\206 FEV 1 , 2.4L (80% predicted normal) \227\206 VC, 2.9L (83% predicted normal) \227\206 FEV 1 /VC ratio, 83% \227\206 Hb, 11.7g/dL \227\206 MCV, 89.5fL \227\206 Neutrophils, 6.21 \227 10 9 /L \227\206 Lymphocytes, 1.03 \227 10 9 /L \227\206 Eosinophils, 0.86 \227 10 9 /L \227\206 CRP, 159mg/L \227\206 ESR, 89mm/h \227\206 Sputum, profuse growth of Streptococcus pneumoniae \227\206 ANA/ANCA, negative \227\206 CXR, declined, as pregnant \227\206 Urinalysis, negative \227\206 Free thyroxine, 14.6pmol/L (11.5 \200\22322.7) \227\206 Renal function, normal. Question 30a) What are the most likely diagnoses? CASE HISTORIES IN RESPIRATORY MEDICINE 244 Answer 30a) What are the most likely diagnoses? Asthma is the most likely diagnosis, given the previous history of salb- utamol and beclome thasone responsive wheeze. Her normal spirometry is a little unexpected given the wheeze on examination, but she was using inhaled bronchodilators and steroids regularly. There is cl ear evidence of superadded infection with crackles, raised CRP and profuse Streptococcus pn eumoniae in the sputum. Progress She was treated with 14 days of amoxicillin, continuing inhaled salmeterol and flixotide (o ral steroids were not considered necessary), making a moderately rapid recovery. Two weeks later she had fully recovered. Investigations \227\206 Neutrophils, 4.73 \227 10 9 /L \227\206 Lymphocytes, 1.86 \227 10 9 /L \227 \206 Eosinophils, 1.35 \227 10 9 /L \227\206 CRP, 24mg/L, falling to <8 one month later \227\206 ESR, 51mm/h \227\206 ANA/ANCA, negative. The rest of her pregnancy was uneventful apart from another chest infection with cough, fev er, chest pain and wheeze; the sputum grew a fully sensitive Haemophilus influenzae and she responded to amoxicillin. Progress Two months post-partum she presented again with malaise, fever, night sweats, weight loss, haemoptysis, cough and wheeze. She had had a brief episode of whole body urticaria, a few i tchy cutaneous nodules and a small sub-lingual ulcer with raised edges. Investigations \227\206 SaO 2, 90% \227\206 Hb, 13.4g/dL \227\206 Platelets, 669 \227 10 9 /L \227\206 Neutrophils, 8.43 \227 10 9 /L CASE 30 245 \227\206 Lymphocytes, 2.75 \227 10 9 /L \227\206 Eosinophils, 5.33 \227 10 9 /L \227 \206 CRP, 182mg/L \227\206 ESR, 96mm/h \227\206 ANA/ANCA, negative \227\206 Aspergillus , negative precipitins \227\206 Urinalysis, normal \227\206 Renal function, normal \227\206 Total IgE, 451kU/l (5 \200\223120) \227\206 Sputum, profuse growth of Haemophilus influenzae and Moraxella catarrhalis \227\206 CXR Fig. 30.1. Fig. 30.1 CXR. Questions 30b) What additional diagnosis should now be considered? 30c) Which features support, and which do not, this additional diagnosis? CASE HISTORIES IN RESPIRATORY MEDICINE 246 Answers 30b) What additional diagnosis should now be considered? Churg Strauss syndrome (CSS) or other eosinophilic lung disease. 30c) Which features support, and which do not, this additional diagnosis? The eosinophil count is over 10 times the upper limit of normal, and is unlikely to be due to asthma alone. Levels in excess of 1.5 times normal are usually seen in CSS. The elevated inflammatory markers would be compatible with infection alone. Cutaneous features are seen in up to 80% of patients with CSS, e.g. urticaria and subcutane ous nodules. Fever and weight loss are equally common. The tongue base ulcer could be vascu litic, but there is limited other evi- dence of active vasculitis. Urinalysis showed no blo od or protein and the blood markers of vasculitides were negative, renal involvement can be absent in over 50% of cases of CSS. Other recognized complications of CSS, such as sinusit is, rhinitis, mono-neuritis multiplex, and pericardi- tis, were absent. Progress The patient declined a bronchoscopy. An HRCT scan was considered insuffi- ciently likely to alter management to justify exposing her to the significant extra risks of irradiating lac tating breast tissue. A dose of 40mg of oral pred- nisolone produced a dramatic clinical re sponse within days, the SaO 2 rose to 98%, and the CXR, CRP and ESR returned to normal with in a month. The eosinophil count fell to 0.23 \227 10 9 /L within a week, and 0.08 \227 1 0 9 /L within 2 months. Over the subsequent year her steroid dose fluctuated, but rarely went below 10 mg/day. She had repeated sputum-positive chest infections that responded rapidly to antibiotics. Her st eroid dose was slowly reduced to 5mg/day. Six months later, her systemic symptoms returned with an eosinophil count of 7.7. Urinalysi s was positive for blood and protein (although renal function remained normal). ANA and ANC A remained negative. FEV 1 /VC was 3.5L/3.8L (>100% predicted). Prednisolone was increased to 50 mg a day. CASE 30 247 Questions 30d) Should this further development surprise you? 30e) What further tests might be helpful? 30f) What alternative disease-modifying therapies might be considered? 30g) What additional medications should be considered? 30h) Compare the repeat spirometry with that done originally, what does this suggest might have been present the first time? 30i) What is the likely prognosis? CASE HISTORIES IN RESPIRATORY MEDICINE 248 Answers 30d) Should this further development surprise you? No, the evolution of Churg Strauss (defined as asthma, hypereosinophilia and small vessel v asculitis with granuloma) in this patient is typical. It tends to be a three-phase disease. The initial phase is usually atopic asthma alone (with or without sinusitis/rhinitis). The second phase, months or a few years later, is associated with a rising eosinophil count; t his is often the first clue that the problem is more than just asthma. A rising eosinophil count is probably more useful than a single raised value that can occur in asthma anyway, a lthough >1.5 times normal is an accepted cut-off. The third phase is the onset of vasculiti s, which again can be months or years later. 30e) What further tests might be helpful? The diagnosis is fairly secure without further tests. The absence of a positive ANCA (or an ti-myeloperoxidase, MPO) does not greatly reduce diagnostic confidence, as it is positive i n only 40 \200\22370% of patients. A renal biopsy may be appropriate in doubtful cases (par ticularly if there is an abnormal urinary sediment), or biopsies from alternative sites of involvement, such as skin or upper airway lesions (in retrospect a biopsy of the tongue ulc er would have been easy and safe). Renal biopsy is likely to be abnormal in the presence of haematuria, and carries only a small risk; a focal, segmental, necrotizing glomerulonephri tis is usually seen. Chronic eosinophilic pneumonia is an alternative diagnosis (see case 1 8) although a vasculitis is not seen; an apparent chronic eosinophilic pneu- monia can evol ve into CSS. However, further investigations to detect other potentially serious complications should be done. ECG and cardiac ultrasound may detect coronary vasculitis, with pericarditis and hea rt failure, which contributes to about half the deaths. In the absence of relevant symptoms (diarrhea, bleeding, abdominal pain) routine gastro-intestinal investigations are not nece ssary. If the diagnosis is secure, the response to steroids is classi- cally rapid and furt her tests may be pointless and delay treatment. 30f) What alternative disease-modifying therapies might be considered? The aggressiveness of \200\230remission-induction \200\231 therapy will depend on the seve rity and extent of the vasculitis, and may require additional immu- nosuppression with cycl ophosphamide, particularly if there is significant renal, cerebral, gastro-intestinal or ca rdiac involvement. This is not often seen in Churg Strauss syndrome, compared to Wegener \200\231s granulomatosis, CASE 30 249 for example. However, steroid-sparing agents should be considered once remission has been a chieved. Potential immunosuppressants for maintenance therapy could be either daily azathioprine (wi th careful monitoring of white cell counts and liver function) or weekly methotrexate (with careful monitoring of bone marrow, liver and renal function). Disease activity can be moni tored by symptoms, eosinophil count, urine haematuria/proteinuria, CRP and ESR. Specific ma rkers, such as ANCA/anti-MPO, can remain high Fig. 30.2 Birmingham vasculitis activity score (BVAS). CASE HISTORIES IN RESPIRATORY MEDICINE 250 despite successful remission, and levels may also lag behind during an exacerbation. Generic symptom and sign scores to assess vasculitis have been devel- oped and are a useful aide-m moire ( Fig. 30.2 ). 30g) What additional medications should be considered? Other therapies to consider are for bone protection, calcium and vitamin D, and/or biphosph onates. 30h) Compare the repeat spirometry with that done originally, what does this suggest might have been present the first time? The improved spirometry indicates the original values were \200\230restrictive \200\231. A CXR then would probably have had an infiltrate (infective or eosinophilic). 30i) What is the likely prognosis? Overall 5-year survival rate is over 70% for Churg Strauss, better than Wegener \200\231s o r microscopic polyangiitis. Relapse rates are about 20%. Complications of therapy can be mo re problematic than the disease itself. Further reading Brown K ( 2006 ). Pulmonary vasculitis . Proc Am Thorac Soc ; 3 : 48 \200\223 57 . D \200 \231Cruz DP , David P , Barnes NC ( 1999 ). Difficult asthma or Churg-Strauss syndrome? BMJ ; 318 : 475 \200\223 476 . Case 31 A 24-year-old female classroom assistant, who had immigrated to the UK from Pakistan 10 yea rs previously, presented with a persistent productive cough, with yellow sputum, of 2 month s \200\231 duration. She was 33 weeks pregnant. Auramine staining of three sputum samples r evealed moderate numbers of acid fast bacilli. Questions 31a) What would you do next? 31b) What are particular points you need to consider relevant to her preg- nancy and subsequent delivery? CASE HISTORIES IN RESPIRATORY MEDICINE 252 Answer 31a) What would you do next? Management of open (infectious) pulmonary TB in this case requires close attention to sever al factors: \227\206 Source case isolation. Segregation can be done out of hospital, if multi- drug re sistant TB (MDR-TB) is not suspected, and cases are advised to remain in the confines of th eir home until 2 weeks of appropriate treatment have passed. Current NICE guidelines advise against unnecessary hospitalization. However, if admission i s indicated (e.g. poor social arrangements), all patients with open pulmonary TB should be nursed separately from immunocompromised patients, either by admission to a single room on a separate ward, or in a negative pressure room on the same ward. Smear-positive TB patient s usually rapidly become non-infectious on initiation of adequate treatment, despite presen ce of bacilli in the spu- tum as these may simply be dead organisms. \227\206 Notification. All forms of Mycobacterium tuberculosis are compulso- rily notifiab le under the Public Health (Control of Disease) Act 1984, whereas non-tuberculous mycobacte rial infections are not. The doc- tor who confirms the diagnosis, or makes the decision to treat, is legally responsible for notifying the Consultant in Communicable Disease Control (CCDC) \200\224Health Protection Agency \200\224in England and Wales, or the equivalent Dir ector of Public Health in Scotland and Northern Ireland. It is also advisable to inform the local TB nurse specialist who will be responsible for contact tracing, monitoring of patie nt compliance, administering directly observed therapy (DOT), if necessary, and ensuring co ntinuity of treatment. Notification also allows identification of epidemiological trends an d outbreaks. \227\206 Contact tracing. A complete and thorough contact investigation is important to pr otect contacts from progression to clinically active disease. The TB nurse specialist shoul d initiate a cascade of testing to identify any persons exposed to the source case. Increasing duration and proximity of contact with an infectious case are key determinants o f the likelihood of infection. Close contacts (e.g. family), and casual contacts exposed through the patient \200\231s wor k as a school classroom assistant, should be screened in accordance with the NICE guideline s. All contacts should initially have a Mantoux test if <35y and a CXR if >35y of age. Furt her investigations CASE 31 253 are prompted by whether the contact has had a BCG, together with the result of the Mantoux test (see NICE Clinical Guideline 33, March 2006). \227\206 Clinical treatment. Quadruple therapy should be commenced whilst bacteriological sensitivities are awaited. (This patient has no risk factors for MDR-TB, i.e. previous trea tment for TB, contact with known MDR-TB, HIV infection, failure of clinical response to tre at- ment or prolonged sputum smear positivity). A 6-month regimen comprising rifampicin (R), isoniazid (H), pyrazi- namide (Z) and ethambut ol (E) for 2 months followed by rifampicin and isoniazid for 4 months is advocated for resp iratory disease. The fundamental principle of initiating one bacteriocidal, and one bacteriostatic drug to w hich the mycobacteria are sensitive, still holds true. However, although initiation of thre e agents was previ- ously accepted, the appreciation that current rates of resistance (appr oximately 10% to one drug) are increasing, has led to quadruple therapy being used routinel y. Triple therapy (rifampicin, isoniazid and pyrazinamide) is seldom used, but may be imple mented for patients (with no risk factors for MDR-TB) who are incapable of reporting visual changes which may arise as a consequence of the ethambutol (e.g. learning difficulties, yo ung children). Triple therapy may also be considered if the mycobacteria are proven to be f ully sensitive. Combination tablets, dosage based on patients \200\231 weight, commonly Rifinah (rifampic in/isoniazid) and Rifater (rifampicin, isoniazid and pyrazinamide), may improve patient c ompliance. 31b) What are particular points you need to consider relevant to her preg- nancy and subsequent delivery? TB in pregnancy. \227\206 None of the first-line medications have been shown to be teratogenic and treatment should be instituted with these agents. \227\206 Second-line agents, such as streptomycin and other aminoglycosides, are best avoi ded if possible because of potential fetal ototoxicity. \227\206 Breast-feeding is safe whilst on antituberculosis medications. \227\206 Measurement of liver function tests should be performed prior to treatment in pre gnancy, and post-partum. (Patients with pre-existing liver disease, risk factors for chroni c liver disease, e.g. heavy alcohol intake, and HIV infection should also have pre-treatmen t tests of liver