CASE HISTORIES IN RESPIRATORY MEDICINE 254 function performed.) There is no need to repeat tests during the treat- ment course unless clinically indicated (see question 31f). \227\206 Babies of sputum-positive mothers should receive isoniazid prophy- laxis for 6 we eks, if delivered within 2 weeks of the mother starting antituberculous medication. If a tu berculin skin test at this point is negative, the isoniazid can be stopped and the BCG give n 1 week later. \227\206 The efficacy of the BCG vaccine is debatable and in the UK is estimated to be 70 \200\22380% effective at reducing the chance of a child developing active disease. Few data suggest a benefit over the age of 16y. Neonates born in places where TB is widespread (not ification rate >40 per 100,000), or with 1 or more parents or grandparents born in a high- incidence country, or with a family history of TB within 5 years, should be offered vaccina tion. Progress Quadruple anti-TB chemotherapy was commenced. Three children from the class in which the patient worked had positive Mantoux reactions (8 mm, 11mm and 15mm) following initial screening. Interferon-gamma tests were performed (ELIS pot) \200\224one child \200\231s result was negative, two were positive. CASE 31 255 Questions 31c) What should the patient have been warned about, prior to initiation of the anti-TB medication? 31d) What is the significance of the negative interferon gamma assay? Does this child require chemoprophylaxis? CASE HISTORIES IN RESPIRATORY MEDICINE 256 Answer 31c) What should the patient have been warned about, prior to initiation of the anti-TB medication? The importance of compliance with medication should be stressed. The potential adverse effe cts of antituberculosis medication should be explained (they occur in approximately 10% of patients), although most are mild and do not necessitate discontinuation of treatment. They include: \227\206 Red-orange discoloration of secretions (urine, stool, sweat, tears \200\224 conta ct lenses (may be permanently stained). Monitoring urinary dis- colouration can provide an indirect measure of patient compliance. \227\206 Nausea, vomiting, diarrhea, fever and anorexia. \227\206 Patients should be advised to contact a doctor if they develop: A rash (usually maculopapular but erythema multiforme can develop with isoniazid, and a pho tosensitivity reaction with pyrazinamide) \200\230Flu-like \200\231 symptoms (rifampicin-induced) Bruising (rarely blood dyscrasias arise as a result of isoniazid, and thrombocytopenia due to ethambutol). \227\206 Patient should stop their medication and contact their doctor or TB specialist nurse urgently if they notice: Jaundice Visual disturbance \200\224red/green color blindness, blurring, loss of vision or pain (opt ic neuritis may be secondary to ethambutol 0.3%) Peripheral sensory changes e.g. numbness (neuropathy rarely due to isoniazid). \227\206 Rifampicin and isoniazid (and related compound preparations) are best absorbed on an empty stomach (half an hour before food). Pyrazinamide and ethambutol can be taken at a ny time. \227\206 Drug interactions are common. Isoniazid is a liver enzyme inhibitor and increases the blood level of drugs metabolized by the liver. Rifampicin induces liver enzymes and th ereby decreases the effective- ness of drugs metabolized hepatically, e.g. warfarin, contra ceptive pill. \227\206 Pyridoxine is given if there is a high risk of peripheral neuropathy, i.e. in diabetes, HIV infection, alcohol dependency or renal failure. 31d) What is the significance of the negative interferon gamma assay? Does this child require chemoprophylaxis? The negative ELISpot result, indicates that the Mantoux response was a false-positive in th is instance (probably representing prior vaccination, CASE 31 257 or exposure to environmental mycobacteria). If the child had had expo- sure to MTB, then an appropriate T cell response against the ESAT-6 and CFP-10 proteins from the organism would have been mounted, and a positive ELISpot seen. Further investigation is unnecessary in th is child. In the past, difficulties in determining the significance of a positive Mantoux t uberculin skin test (TST) were commonly encountered, i.e. whether it reflected active or la tent Mycobacterium tuberculosis infection, or a response to either previous BCG administrat ion, or environmental mycobacteria. (Since the tuberculin solution contains a crude mixture of >200 Mycobacterium tuberculosis proteins, of which some antigens are shared with other mycobacteria besides Mycobacterium tuberculosis .) Recent advances in mycobacterial genomics have isolated two proteins \200\224 early secreto ry antigenic target-6 (ESAT-6) and culture filtrate protein-10 (CFP-10) \200\224within a st retch of DNA (denoted region of difference-1 ) of Mycobacterium tuberculosis , which are no t present in the BCG vaccina- tion or environmental mycobacteria. These proteins are strong targets for T helper cells of patients with Mycobacterium tuberculosis infection. Measurem ent of the specific T-cell response to these antigens is now pos- sible via an ELISpot assa y (T-SPOT.TB; Oxford Immunotec) or enzyme- linked immunosorbent assay (ELISA \200\224Quanti FERON-TB test; Cellestis). T cells from individuals with latent Mycobacterium tuberculosis infection become sensitized to ESAT-6 or CFP-10 in vivo ; when the T cells re- encounter th ese antigens ex vivo in the overnight ELISpot or ELISA tests, they release a cytokine, inte rferon (IFN)- . In the ELISpot test, each sensi- tized T cell gives rise to a dark spot, w hich is counted by an automated reader. The ELISA test measures the IFN- concentration in the supernatant of a sample of diluted whole blood after 24h of incubation with ESAT-6 and CFP-10. The response is independent of the subject \200\231s BCG status. To date, the main use of these tests has been in the diagnosis of latent Mycobacterium tuberculosis infectio n, although further indications are being investigated. Progress In the two positive cases, both had normal clinical examinations and CXRs. Chemoprophylaxis was given with 3 months of rifampicin and isoniazid (an alternative is 6 months of isoniaz id). Four days later, the index patient re-presented with 24h of general malaise, nausea and anorexia. She had been compliant with her medication. Question 31e) What would you do next? CASE HISTORIES IN RESPIRATORY MEDICINE 258 Answer 31e) What would you do next? Gastro-intestinal side effects of anti-TB medication are well recognized. Initial advice to take the drugs with or after food may help to ease symp- toms, as can adm inistration at a different time of day, e.g. before going to bed rather than in the morning . Liver function should be tested as non-specific gastro-intestinal symp- toms may reflect dr ug induced hepatitis. (A pregnancy test should also be performed, if this is a possibility, in women of child-bearing age with persisting nausea.) CASE 31 259 Progress Repeat blood tests (day 4 of treatment) showed: Hb 9.4g/dL, MCV 71.7fL, WBC 7.8 \227 10 9 /L, INR 1.1, bilirubin 10 mol/L, ALT 82IU/L, ALP 209IU/L, Alb 39g/L and CRP 82mg/L. Despite taking the tablets with food over the next few days, her nausea wors- ened and she began to vomit. Concern regarding her poor oral intake was expressed by the obstetricians a nd she was admitted to hospital for intravenous fluids. Repeat blood tests (day 7) were per formed. Hb 10.4g/dl, WBC 9.2 \227 10 9 /L, platelets 225 \227 10 9 /L, INR 1.1, Urea 7.6mmol/L, Cr 58 mol/L, bilirubin 13 mol/L, ALT 431 IU/L, ALP 299 IU/L, Alb 37g/L. Questions 31f) What is the most likely explanation for the abnormal LFTs? 31g) What would you do next? \227\206 Stop the rifampicin \227\206 Stop rifampicin and isoniazid \227\206 Stop all the medication \227\206 Stop the current medication and start an alternative anti-TB agent \227\206 Continue the medication but repeat the blood tests in 1 week. 31h) How should she be managed in hospital? CASE HISTORIES IN RESPIRATORY MEDICINE 260 Answers 31f) What is the most likely explanation for the abnormal LFTs? A rise in hepatic transaminases is not uncommon following initiation of TB chemotherapy. Pa rticular risk groups for derangement of liver func- tion include those with known underlyin g liver disease, such as alcohol dependency, cirrhosis and hepatitis B or C, malnourished p atients, and possibly the elderly, children and those taking herbal therapies. Current recommendations suggest: \227\206 If the AST or ALT rise is <2 \227 normal, repeat liver function at two weeks. If levels have fallen, further tests are only required if symptoms occur. \227\206 If the repeat test shows levels \211 2 \227 normal, liver function should be monitored weekly for 2 weeks, then 2-weekly until normal. If transaminase levels are \211 5 \227 normal, or \211 3 \227 normal with clinical symp toms (i.e. \200\230flu-like \200\231 symptoms, nausea, vomiting or anorexia), the rifampic in, isoniazid and pyrazinamide should be stopped. However, sustained treatment with a singl e agent should never occur. Hepatitis serology, if clinically indicated, for co-existent viral hepatitis should be considered. 31g) What would you do next? \227\206 Stop the rifampicin \227\206 Stop rifampicin and isoniazid \227\206 Stop all the medication \227\206 Stop the current medication and start an alternative anti-TB agent \227\206 Continue the medication but repeat the blood tests in 1 week. In the case of smear-positive disease within 2 weeks of starting treat- ment, an alternativ e treatment should be given until liver function returns to normal. Close liaison with the local microbiology or infection control, or public health team, is prudent. Streptomycin is often used for this indication alongside ethambutol. Newer agents to consid er include fluoroquinolones (e.g. levofloxacin or moxifloxacin). In this case, at 33 weeks of pregnancy, the risks must be weighed against the need for treatment. The risk of potenti al fetal oto- toxicity is greatest from streptomycin (but is increased with all aminogly- c osides) and within the first trimester. If a patient becomes pregnant or is found to be pre gnant whilst taking streptomycin, it should be discon- tinued, if possible. In this case, t he risks of untreated disease outweighed CASE 31 261 those of streptomycin and this was commenced with ethambutol. Renal function monitoring is required. 31h) How should she be managed in hospital? As this patient has received <2 weeks of treatment she is potentially infectious. \227\206 Segregation from other patients is required until 2 weeks of treatment is complet e. A face mask should be worn if she leaves isolation, i.e. to go to radiology or other are as where contact could be made with sus- ceptible individuals (including young infants). \227\206 Ideally all patients should be nursed in a negative pressure room. However, if on a ward with no immunosuppressed patients, a single room vented to the air outside would be suitable. If the ward had immunosuppressed patients or the risk of MDR-TB was high, a nega - tive pressure room is essential. \227\206 Staff and visitors should wear masks if in contact with patients with poten- tial open pulmonary MDR-TB or where aerosol generating procedures, e.g. bronchoscopy or sputum induction techniques are being performed. \227\206 Re-introduction of the medications. (This can be done without the need for altern ative therapy, in the period awaiting return to normal- ity of the liver function, if patie nts are smear negative or >2 weeks into their treatment course.) Incremental drug re-introd uction strategies vary between different centers with no universally agreed approach. Sever al regimes add drugs every 3 days if the problem is fever, rash or vomiting; however, liver function derangement often takes longer to respond and requires longer intervals between e scalation. Once liver function is normal, sequential introduction of the original drugs can be made with daily clinical review and liver function testing in the fol- lowing order: 1st: isoniazid 50mg/day, titrating up to 300 mg/day after 2 \200\2233 days if no reaction o ccurs, this is then continued. Isoniazid is postulated to induce hepatic injury via an idio syncratic hypersensitivity reaction which may be dose-dependent. The exact mechanism, howev er, remains unclear, although it can safely be re-introduced once the liver function return s to baseline. 2nd: after 2 \200\2233 days, if stable, rifampicin 75 mg/day can be started, increasing to 300 mg after 2 \200\2233 days if no deterioration. Reintroduction is safe, if liver functio n and clinical parameters remain normal. Serious liver injury is rare; however; rifampicin CASE HISTORIES IN RESPIRATORY MEDICINE 262 does increase the hepatotoxicity of isoniazid, probably via enzyme induction and elevation of toxic metabolite concentrations, which explains in part the reason for re-initiation of the latter agent first. Finally: pyrazinamide 250mg/ day, increasing to 1g after 2 \200\2233 days, and then to 1.5g (<50 kg) or 2g (>50kg). If the transaminases rise when pyrazinamide is restarted, the drug should be avoided as cases of potentially fatal hepatic necrosis have been reported. If there is no deterioration, the medication can be continued and the streptomycin stopped. If a further reaction occurs to pyrazinamide, then rifampicin and isoniazid for 9 months, w ith ethambutol for the initial 2 months, should be given. Progress Re-introduction of quadruple therapy was successful and, after 23 days in hospital, the pat ient was discharged. Her baby was born a week later and, fol- lowing completion of 6 weeks of isoniazid syrup chemoprophylaxis, had a negative Mantoux test and received the BCG vacci nation 7 days later. Further reading Control and prevention of tuberculosis in the United Kingdom: Code of Practice ( 2000 ). Jo int Tuberculosis Committee of the British Thoracic Society . Thorax ; 55 : 887 \200\223 90 1 . Chemotherapy and management of tuberculosis in the United Kingdom: recommendations ( 1998 ). Joint Tuberculosis Committee of the British Thoracic Society . Th orax ; 53 : 536 \200\223 548 . Lalvani A ( 2007 ). Diagnosing tuberculosis infection in the 21st century: New tools to tac kle an old enemy . Chest ; 131 : 1898 \200\223 1906 . Tuberculosis: Clinical Guideline 33 (March 2006 ). National Institute for Health and Clinic al Excellence (NICE) . http://www.nice.org.uk/nicemedia/pdf/CG033FullGuideline.pdf (accesse d 1st September 2009) Case 32 A 66-year-old lady originally presented to the emergency department with gradual onset of s hortness of breath over a week. The relevant past medical history was of asthma, and her fa ther died post-operatively of a pulmonary embolus aged 59. She was very ill with signs of p ulmonary hypertension with a loud P2, raised JVP, tachycardia and hypotension. Her right an kle was mini- mally swollen. ECG showed right bundle branch block and right axis devia- tio n. Breathing air, the PaO 2 was 8.0kPa and the PaCO 2 was 3.4kPa, indicating a large alveol ar to arterial gradient for oxygen (7.8kPa). Her pulmonary arteries were enlarged on CXR. A clinical diagnosis of acute on chronic pulmonary emboli was made, and confirmed on ventil ation/perfusion (V/Q) scanning with multiple and exten- sive unmatched perfusion defects. S he was anti-coagulated and within a week her symptoms had greatly improved. On review in clinic 1 month later, her exercise tolerance was partly back to normal and she was more troubled by cough. She had stopped her inhalers whilst in hospital and they had n ot been restarted. Anti-coagulation had been exemplary. On examination, all signs of pulmon ary hypertension had resolved. Investigations \227\206 Lung function showed a mild obstructive picture and the SaO 2 was 92%. \227\206 Repeat V/Q scan had improved, but showed persisting unmatched perfusion defects. \227\206 A CT pulmonary angiogram 1 month later revealed a thrombus lying in the right mai n pulmonary artery but the rest of the pulmonary vasculature appeared normal, apart from a few sub-segmental emboli in the upper lobes. \227\206 ECG showed resolution of the right-sided abnormalities. \227\206 Cardiac echo showed a right ventricle at 3.9cm (upper limit of normal 3.0cm) with all other chambers normal. Estimation of the peak pulmonary artery pressure (PAP) was tech nically unsatisfactory, but reported as 90mmHg (upper limit of normal = 35mmHg). \227\206 In view of the clinical improvement no further action was taken apart from recommending that the INR was kept between 2.5 and 3.0. CASE HISTORIES IN RESPIRATORY MEDICINE 264 Progress Six months later she returned to out-patients with some deterioration in her shortness of b reath. She had lost 25kg in weight. She had experienced two episodes of central chest pain following exercise, in association with marked breathlessness and felt she was going to pas s out. Warfarin control had been excellent. On examination there was no evidence of pulmonary hypertension and her SaO2 was now 96%. On walking 50m her heart rate rose to 105 and her SaO 2 fell to 86%, with mild shortness of b reath. Repeat cardiac echo showed a mod- erately dilated right ventricle (3.3cm), moderatel y reduced systolic contraction and, again, the peak PAP was difficult to measure, but estim ated to be about 100mmHg. Investigations Further tests were performed 10 months after the initial presentation to eluci- date the ca use of her continuing shortness of breath. \227\206 Shuttle walking distance 150m, SaO 2 fell to 88% \227\206 V/Q scan again showed multiple matched defects Right-sided cardiac catheter data : \227\206 Mean PAP, 29mmHg \227\206 Normal right atrial pressure \227\206 Cardiac output, 4.1L/m \227\206 Mixed venous SO 2 , 51% \227\206 Following pros tacyclin infusion, cardiac output rose to 5.5L/m. CASE 32 265 Questions 32a) What is the most likely diagnosis, should any alternatives be considered? 32b) What might have been the cause of the chest pain and dizziness? 32c) Describe the catheterization data; does the discrepancy with the echo surprise you? 32d) What is the likely untreated prognosis for this patient? 32e) What forms of treatment are available at this stage? CASE HISTORIES IN RESPIRATORY MEDICINE 266 Answers 32a) What is the most likely diagnosis, should any alternatives be considered? The most likely diagnosis is chronic pulmonary thrombo-embolic pulmonary hypertension (CTEP H). The persisting unmatched Q scan perfusion defects strongly suggest this. The cardiac ca theterization abnormalities are not very severe, and, therefore, other possible causes shou ld be considered, including a return of her asthma, for example. 32b) What might have been the cause of the chest pain and dizziness? If pulmonary hypertension is the cause of her chest pain and dizzyness, then right heart an gina and a fall in cardiac output could be occurring on exercise, but is more often seen in primary pulmonary hypertension. Alternatively, if anxiety and hyperventilation were the ca use, then they could be causing these symptoms, but the fall in SaO 2 on exercise clearly r ules out hyperventilation syndrome (case 12). 32c) Describe the catheterization data; does the discrepancy with the echo surprise you? The catheterization data show a mildly raised mean PAP (upper limit of normal about 25mmHg) . The cardiac output is slightly reduced, but the mixed venous SO 2 is curiously low and do es not seem compatible with the SaO 2 and the cardiac output. The echo measurement of PAP i s the peak pressure (systolic) and, therefore, higher than the mean pressure. The echo meth od relies on the conversion of the peak velocity of a regur- gitant tricuspid valve jet dur ing systole into a theoretical peak PAP \200\224this is not always accurate and significant discrepancies occur. 32d) What is the likely untreated prognosis for this patient? Untreated, the prognosis is not clear. Most pulmonary emboli resolve quickly on treatment w ith anti-coagulation. Disappearance of extensive clots within a week has been reported but recent series have shown that over half have detectable residual defects at 3 months. Non-r esolution is associated with gradual deterioration of exercise tolerance and a rise in PAP, after an apparent \200\230honeymoon \200\231 period. The conventionally quoted incidence of this is about 0.5% after an episode of acute pulmonary emboli. However, in one recent st udy, the prevalence of an abnormally high PAP (>40mmHg systolic and >25mmHg mean) was 1% at 6 months, 3% at 1 year and 4% at 2 years, with no further increase thereafter. Once this p rocess of a persistent and rising pressure is established, it is believed CASE 32 267 that progression to death is almost inevitable without treatment. Prognosis correlates with current PAP; a 50% 10-year survival with mean pressures between 30 and 40mmHg, but only a 20% 2-year survival if the pressure is over 50mmHg. 32e) What forms of treatment are available at this stage? Treatment consists mainly of maintaining adequate anti-coagulation and the use of pulmonary -specific vasodilators. Choice of vasodilators used to be based on the results of acute stu dies but these do not accurately predict long-term response and, in practice, various drugs are tried. Calcium channel blockers are used extensively. Long-term oxygen may have a role , even in mild hypoxia. The mechanism of progression from acute emboli to a chronic deteriorating condition is not understood. There are probably three components. First, there may be in situ extension of c lot with gradual silting up of the pulmonary tree, although resected specimens show organiz ed thrombi, all of similar age, suggesting little new thrombus is forming. Second, the rais ed PAP may cause remodeling of the distal vascular bed with an increase in vascular resista nce, as is thought to occur in other causes of pulmonary hypertension. Third, if there is s ignificant hypoxia, then this may also provoke further, and eventually irreversible, rises in vascular resistance. Abnormalities of fibrinolysis or throm- botic tendency have not bee n consistently found in these individuals. The factors about the patient that tip the proce ss from resolution to progression are unclear, although a previous embolus, younger age, mo re severe initial embolic event, poor resolution of the Q scan perfusion defects and a high er PAP acutely, all seem to predict higher risk. Some cases have not had a recognizable acu te embolic event. Further investigations and progress Conventional pulmonary angiography showed multiple obstructed lobar and segmental arteries in the right lung, but the left side was largely clear of emboli. A Greenfield IVC filter w as introduced and she was placed on amlodipine 5mg/day. The evidence for a benefit from suc h IVC filters in this situation is very limited. By 18 months post-presentation, her shuttle walking distance had fallen to 360m, SaO 2 fall ing to 89%, but she denied any deterioration in her day-to-day activity levels. Repeat card iac catheterization showed a mean PAP of 63mmHg. At 25 months her PAP was 43mmHg, cardiac o utput 5.4L/m. No pulmonary vasodilation occurred following nitric oxide (NO) inhalation. CASE HISTORIES IN RESPIRATORY MEDICINE 268 (a) (b) (c) Fig. 32.1 (a) \200\223(c) CT pulmonary angiograms. CASE 32 269 Echocardiography 3 years post-presentation showed a right ventricular diameter of 4.2cm and an estimated peak PAP of about 100mmHg. Shortly after this she complained of increased SOB and occasional morning haemoptysis. She was now visibly cyanosed at rest (SaO 2 92%), had a raised JVP (+5cm) with a dominant V wav e, loud pulmonary second sound, parasternal heave and a right ventricular 3rd sound; ECG sh owed right ventricular hyper- trophy. Echo again gave a peak PAP estimate over 100mmHg. Shu ttle walking distance was 430m with the SaO 2 dropping to 84%. Overnight oxygen levels were stable at about 83 \200\22385%, overnight oxygen via nasal prongs was prescribed. Questions 32f) What further treatment options are there for this lady? 32g) What further imaging is required before considering this treatment? 32h) Does the CTPA (Fig. 32.1) suggest this treatment would be appropriate? 32i) What is the main risk of this treatment? 32j) What would you do? 32k) Could anything have been done to prevent this complication occur- ring at the time of the original pulmonary embolus? CASE HISTORIES IN RESPIRATORY MEDICINE 270 Answers 32f) What further treatment options are there for this lady? Further attempts to lower PAP could include the newer pulmonary artery vasodilators, includ ing prostacyclin analogs (epoprostenol, beraprost, iloprost), endothelin receptor antagonis ts (bosentan, sitax- sentan, ambrisentan) and phospho-diesterase-5 inhibitors (sildenafil), although not all these drugs are licensed for this purpose. Preliminary evidence (no RCTs) suggests they lower PAP and improve exercise toler- ance. The most successful therapy, in a carefully selected subgroup, is pulmonary thrombo-endarterectomy. Organized thrombi in ma in and lobar vessels are removed by careful dissection along a plain between the arterial w all and the occluding mass. Skilled surgeons can extend the endarterectomy into segmental l evel. Surgical success clearly depends on skill and experience. 32g) What further imaging is required before considering this treatment? Surgical success also depends on there being significant resectable organ- ized thrombus, r ather than more distal secondary vascular changes, as the cause for the increased vascular resistance. Pulmonary angiography, preferably conventional as well as MRI, helps define the resectable tissue. In addition, Q scans may help; with significant thrombi the scan shows (a) Unperfused lung (c) Perfused lung Large pulmonary artery Wall thrombus Rapidly narrowing and then occluded pulmonary artery (b) (d) Mural thrombus (different case) said to be less common in CTEPH Fig. 32.2 (a) \200\223(d) CT pulmonary angiograms. CASE 32 271 clear segmental defects; with secondary distal vascular changes, the Q scan abnormalities t end to be very much more diffuse. However, there is a considerable degree of subjectivity i n the interpretation of these scans. 32h) Does the CTPA (Fig. 32.1) suggest this treatment would be appropriate? The CTPA (Fig. 32.1) shows several things. The first slice (a, lung win- dows) shows mosaic perfusion of the lung, implying defects of perfusion, compatible with blocked pulmonary ar teries. The second slice (b) shows sudden narrowing of a left pulmonary arterial branch and then sudden cessation, probably due to occlusion. The third slice (c) is very hard to inte rpret but shows a large main pulmonary trunk (bigger than the aorta) and probable organized thrombus lining the right proximal pul- monary arteries, which in theory could be resectab le. The angiographic appearance of resectable disease results from the complex interplay be tween occlusion and recanalization. Thus chronic thrombi appear dif- ferent to acute thromb i, with webs traversing lumina, intimal irregulari- ties, pouch-like defects, abrupt narrow ing of vessels, often at branch origins, and the absence of apparent intraluminal filling d efects. 32i) What is the main risk of this treatment? Thrombo-endarterectomy carries a significant in hospital mortality, approximately 5 \200 \22320%, depending on center and surgeon experience. Risk is increased in those over 70, ob esity, co-morbid disease (e.g. COPD, ischaemic heart disease and renal failure), right vent ricular failure (i.e. raised right atrial pressures) and possibly the duration of pulmonary hypertension. The main immediate complication is re-perfusion pulmo- nary oedema, perhaps similar to high altitude pulmonary oedema. Following removal of the thrombus, PAP may remai n higher than normal and feed through to unprotected capillaries leading to wall damage, pu l- monary oedema and hemorrhage. 32j) What would you do? The operative decision is difficult given the unpredictable rate of decline, uncertainty ov er operability and the immediate in-hospital mortality. 32k) Could anything have been done to prevent this complication occur- ring at the time of the original pulmonary embolus? The place of thrombolysis in acute massive PE, in the absence of circulatory compromise, is not yet established. There is little evidence that throm- bolysis of big clots will reduce progression to CTEPH. CASE HISTORIES IN RESPIRATORY MEDICINE 272 Fig. 32.3 Thrombo-endarterectomy specimens, from a different case, removed during surgery ( courtesy of Dr Keith McNeil). Further progress Five years post-presentation this lady had a pulmonary artery thrombo- endarterectomy (Fig. 32.3) after a repeat conventional pulmonary angiogram had suggested the prospect of a good result. Three months post-operatively her resting saturations were normal at 98% on air. Shuttle wa lk was 420m with a drop in SaO 2 to 92%. Echo showed unchanged right ventricular dimensions , and there was no tricuspid regurgitation to estimate pressures. Six months post-operatively (5 years after her initial PEs), mean PAP was measured directly at 18mmHg. Ten years post-presentation, and 5 years post-operatively, shuttle walking distance was 560 m, resting SaO 2 96%, and remained at 96% on exercise. Echo-derived peak PAP was 34mmHg (at the upper limit of normal). This is a remarkable result and increasingly this is the outcome of thrombo- endarterectomy in carefully selected cases of CTEPH performed in highly specialized centers. Further reading McNeil K , Dunning J ( 2007 ). Chronic thrombo-embolic pulmonary hypertension (CTEPH) . Heart ; 93 : 1152 \200\223 1158 . Pengo V , Lensing AW , Prins MH , Marchiori A , Davidson BL , Tiozzo F et al . ( 2004 ). Th rombo-embolic Pulmonary Hypertension Study Group Incidence of chronic thromboembolic pulmon ary hypertension after pulmonary embolism . N Engl J Med ; 350 : 2257 \200\223 2264 . Segovia Cubero J , Ortiz Uribe JC , G mez Bueno M , Mo ivas Palomero V , Gonz lez Gonz lez M , Alonso-Pulp n Rivera L ( 2007 ). Role of bosentan in patients with chronic v enous thrombo-embolic pulmonary hypertension . Med Clin (Barc) ; 128 : 12 \200\223 144 . Case 33 A 71-year-old lady was referred to the respiratory clinic with a history of non- resolving pneumonia. She had presented to her GP 3 weeks previously with cough, fevers and myalgia, a nd despite courses of amoxicillin and erythromycin, she was not improving. On direct questi oning, there was a 3-month history of progressive dyspnoea and a dry cough. She had been se en by her GP four times over the last 6 months and treated with antibiotics for chest infec tions on each occasion. Her past history included controlled epilepsy, and bilateral knee replace- ments for osteoa rthritis several years ago. She was a lifelong non-smoker with pigeons living in her roof s pace, but with no other personal or family history of note. Her current medication included phenytoin, paracetamol and diclofenac. On examination she was sweaty, although afebrile. She was tachypnoeic (22/min) at rest, her oxygen saturations were 93% and on examination of the chest she had bilateral fine crackle s at the bases with no other signs of cardiac decompensation. Routine blood tests \227\206 Hb, 13.9g/dL \227\206 WCC, 15.4 \227 10 9 /L \227\206 Platelets, 315 \227 10 9 /L \227\206 Neutrophilia, no eosinophilia \227\206 Urea and electrolytes normal \227\206 CRP, 57mg/L \227\206 ESR, 43mm/h. Pulmonary function tests FEV1/(L) FVC (L) 1.42 L (75% predicted) 1.87L (79% predicted) FEV1/FVC ratio 76% CXR s from 2 months ago (a) and from this episode (b) are shown in Fig. 33.1 . CASE HISTORIES IN RESPIRATORY MEDICINE 274 (a) 2 months previously (b) Current Fig. 33.1 CXRs CASE 33 275 Questions 33a) Interpret the CXRs ( Fig. 33.1a and b ). 33b) What is the differential diagnosis? 33c) Justify your choice for the next two most relevant investigations. CASE HISTORIES IN RESPIRATORY MEDICINE 276 Answers 33a) Interpret the CXRs ( Fig. 33.1a and b ). The CXRs show bilateral multifocal consolidation. This appears to be worse in the current C XR ( Fig. 33.1b ) compared to 2 months ago ( Fig. 33.1a ). The infiltrates appear to show a lower zone and peripheral predominance. In addition, these changes are observed in the con text of radiologically preserved lung volumes (i.e. no volume loss). 33b) What is the differential diagnosis? The differential diagnosis is that of multifocal consolidation. In this specific case, infe ction with pneumonoccous or \200\230typical \200\231 bacterial pneu- monia is an unlikely cause \200\224the timeframe is too long and the CXR is not consistent (with bilateral chang es and non-resolution despite appro- priate antibiotic therapy). Certain forms of infective pneumonia should be considered in this context (e.g. Mycoplasma , Coxiella , Psittacosis ) . TB and atypical mycobacteria are a possibility and she is in a high-risk group; the elder ly and immunosuppressed can present atypically. However, given her presentation with malais e in association with pulmonary infiltrates, cryptogenic organizing pneumonia (COP), eosino philic pneumonia and vasculitis should be considered. In addition, given her history of sei - zures, chronic aspiration may be a possible cause as may drug-induced lung disease. 33c) Justify your choice for the next two most relevant investigations. An HRCT chest is the investigation of choice, and will provide impor- tant information on d ifferential diagnosis. It would be important to assess her peripheral eosinophil count, as this may change the likely diagnosis to include one of the lung infiltrate eosinophilic syn dromes (see case 18) (although not all of these disease entities are associated with a peri pheral blood eosinophilia). Further tests for autoimmune disease may be required, but it wo uld be sensible to establish the pulmonary diagnosis first. A bronchoscopy with BAL would b e a reasonable investi- gation, should there be doubt about the radiological pattern on CT, permitting exclusion of infective and malignant disease. Bronchoalveolar carcinoma (BAC) i s a possibility, however the clinical presentation is inconsistent with this diagnosis CASE 33 277 Progress The patient proceeded to HRCT (see Fig. 33.2 ). (a) (b) (c) (d) Fig. 33.2 (a) \200\223(d) HRCT chest. Questions 33d) Describe the HRCT findings (Fig. 33.2). 33e) What is the most likely diagnosis and why? 33f) Describe the histology that is associated with this condition. 33g) How would you investigate this patient further? CASE HISTORIES IN RESPIRATORY MEDICINE 278 Answers 33d) Describe the HRCT findings (Fig. 33.2). There are areas of ground glass and consolidation in all CT slices shown (Fig. 33.2), which appear to be predominant (in the lower slices, b and d) in a subpleural distribution. On t he lowest slice (Fig. 33.3), the consoli- dation is centered around the associated bronchus (i.e. \200\230bronchocentric \200\231). There are a few small nodules and the bronchial w alls appear thickened and dilated. There is a marked absence of other changes, specifically there does not appear to be any areas of fibrosis (e.g. no traction dilata- tion of the ai rways) or gross lymphadenopathy. Fig. 33.3 Enlarged area of CT scan from Fig. 33.2d. 33e) What is the most likely diagnosis and why? The most likely diagnosis is cryptogenic organizing pneumonia (COP), due to the combination of clinical and radiological features. Typical fea- tures of COP are as follows: \227\206 Presentation. COP typically presents as a flu-like or infective illness, and is o ften misdiagnosed and treated as bacterial pneumonia with repeated courses of antibiotic th erapy. Typical symptoms at pres- entation include respiratory symptoms (cough and shortness of breath) but also constitutional symptoms (malaise, fatigue, sweats, fevers and weight l oss (seen in over 50% of cases). COP is not smoking-related. \227\206 Radiology. Bilateral diffuse alveolar opacification in the presence of nor- mal l ung volumes (as seen here) is typical. Evidence of chronic fibrosis CASE 33 279 ( \200\230honeycombing \200\231) is usually not observed at presentation. However, several different radiological patterns are recognized including: \200\230Typical COP \200\231 \200\224multiple alveolar shadows \200\230Focal COP \200\231 \200\224a solitary opacity \200\230Infiltrative COP \200\231 \200\224infiltrative appearing opacities Migratory infiltrates over time Peripheral infiltrate predominant Cavitation and pleural effusion are rarely seen. The CT appearances are usually characteristic, although differentia- tion from eosinophilic lung disease, drug induced lung disease and carcinoma may not be possible. \227\206 Other tests. As seen here, an associated increase in inflammatory markers is the norm, but is non-specific. Auto-antibodies are typically negative. Lung function typically shows mild to moderate restriction, and impairment of gas exchange manifested as a resting hypoxia and a widened Aa gradient. \227\206 Differential diagnosis. Organizing pneumonia may be primary (cryptogenic) or seco ndary and can be associated with malignancy or connective tissue disease (especially polymy ositis/dermatomyositis). Although COP is the most likely diagnosis, other possibilities in this case include: Bacterial infection \200\224this is unlikely in this case, as the history is of several mon ths, the changes are bilateral and progressive and there has been no response to reasonable therapy. Eosinophilic pneumonia \200\224(see case 18) bilateral symmetrical infil- trates raises the possibility, but a more peripheral distribution and associated peripheral eosinophilia wou ld be expected. Hypersensitivity pneumonitis (HP) \200\224(see case 8) the radiological appearance on CXR a nd CT is not typical here (acutely, HP would produce diffuse ground glass and centrilobar n odules, whereas chronically fibrosis would be seen). There is a potential antigen (the pige ons in the loft), so this should be considered and excluded. Drug-induced lung disease \200\224this patient is on anti-epileptics, which are a recognize d cause of lung disease. However, there are no new or recently introduced medications and, although drug-induced disease may take on a variety of radiological patterns including the one seen here, this seems unlikely. CASE HISTORIES IN RESPIRATORY MEDICINE 280 Interstitial lung disease associated with connective tissue disease \200\224 there are, aga in, no pointers toward a co-existing connective tissue disease; however, the possibility sh ould be considered and investi- gated. Most commonly, a UIP-type picture of lung disease is seen in association with connective tissue disease; however, COP is reported in associatio n. Acute lung injury \200\224in the absence of a clear precipitant, this is unlikely here. 33f) Describe the histology that is associated with this condition. COP produces a distinct histopathological pattern, which is characterized by proliferation of granulation tissue within the small airways ( \200\230intralu- minal buds \200\231), ass ociated with chronic alveolar inflammation (hence a bronchocentric pattern is seen on CT). This combination is referred to as \200\230organizing pneumonia \200\231. Fibrosis and lun g destruction is typically absent, as is vasculitis or granuloma formation.