The CXR (Fig. 17.1) shows increased cardiothoracic ratio and a small right pleural effusion , but the lung fields and mediastinal contours are unremarkable. The ECG (Fig. 17.2) shows sinus rythym with right axis deviation and right ventricular hypertrophy (dominant R wave i n V1, deep S waves V4 \200\2236) 17c) What is the clinical diagnosis and what particular underlying causes should be considered? Pulmonary hypertension (PH). The main causes to consider in this patient are sarcoidosis as a direct cause, and thrombo-embolic disease. CASE 17 139 17d) Give two key investigations that must now be performed. \227\206 CTPA. The patient has underlying, albeit localized, prostatic malig- nancy, which would put him at risk for the development of pulmo- nary emboli and chronic thromboembolic pulmonary hypertension (CTEPH). \227\206 Echocardiogram. To confirm the diagnosis and degree of PH, and to exclude left he art disease or intracardiac shunting as a contributory factor to the PH. Further investigation Echo confirmed PH with estimated pulmonary artery systolic pressure of >100mmHg. Right vent ricular systolic function was severely impaired. There was right atrial enlargement, with t ricuspid regurgitation. The left heart was normal in appearance with normal left ventricula r systolic function and no evidence of any intracardiac shunts. A small pericardial effusio n was seen. CASE HISTORIES IN RESPIRATORY MEDICINE 140 (a) (b) Fig. 17.3 CTPA. CASE 17 141 (a) (b) Fig. 17.4 Selected cuts from CT of 2005 for comparison. Questions 17e) What are the key abnormalities on the CTPA and how does this examination differ from that of 2005? 17f) What action and further investigations are now required? 17g) Give five mechanisms by which sarcoidosis can cause PH. CASE HISTORIES IN RESPIRATORY MEDICINE 142 Answers 17e) What are the key abnormalities on the CTPA and how does this exam- ination differ from that of 2005? The main findings on the CTPA are of pulmonary hypertension \200\224the main pulmonary trun k is enlarged (Fig. 17.5), as are the left and right pulmonary artery. As a consequence of this, there is right ventricular and atrial enlargement. Not shown is tricuspid regurgitati on with reflux of contrast into the inferior vena cava. There is also a small pericardial a nd a right pleural effusion. There is also a very subtle mosaic perfusion appearance to the lung fields (Fig. 17.5). No evidence of either acute or chronic thrombo-embolic disease wa s seen. Finally, no hilar or mediasti- nal lymphadenopathy was demonstrated. In comparison to the scan from 2005, the diffuse ground glass change has all resolved (there is much grea ter contrast between the major airways and parenchyma in the 2005 compared with current sca n \200\223the black bronchus sign). The diffuse cen- trilobar nodules have also resolved. T he current CT, therefore, shows no evidence of active parenchymal sarcoidosis. 17f) What action and further investigations are now required? Referral to a pulmonary hypertension center is now needed for cardiac catheterization studi es and consideration of specific therapy for PH. The precise cause of the patients PH is no t clear at this point. Sarcoidosis remains a possibility but the patient now requires full investigation to exclude alternative causes of PH. Further investigations that could be org anized pending review in a PH center would be: \227\206 V/Q scan. Although the CTPA shows no central or segmental emboli, in unexplained PH a Q scan is performed as a more sensitive measure of peripheral embolic disease. Mosaic perfusion with paucity of blood vessels giving slightly darker appearance compared t o rest of lung fields Pulmonary trunk larger than ascending aorta at same level Fig. 17.5 Detail of CTPA image. CASE 17 143 \227\206 Abdominal ultrasound. To exclude porto-pulmonary hypertension (development of pul monary hypertension in association with portal hypertension from cirrhosis). \227\206 HIV test. Pulmonary hypertension is a rare (1%) complication of HIV infection. 17g) Give five mechanisms by which sarcoidosis can cause PH. Mechanisms by which sarcoidosis can cause pulmonary hypertension include: \227\206 Progressive pulmonary fibrosis \227\206 Secondary respiratory failure \227\206 Compression of pulmonary arteries by lymphadenopathy \227\206 Primary vasculopathy \227\206 Pulmonary veno-occlusive disease. The development of PH in sarcoidosis is usually attributed to fibrosis and destruction of p ulmonary vessels in association with progressive parenchymal fibrosis (+/ \200\223 contribu tion from chronic hypoxaemia). Development of pulmonary hypertension at the level of large pulmonary arteries can unusually occur with compression by lymphadenopathy. Diastolic dysfu nction caused by myocardial sarcoidosis has also been reported as a cause of pulmonary veno us hypertension. In the absence of significant interstitial fibrosis, PH can arise from a pri- mary vasculop athy where there is a granulomatous vasculitis involving veins and arteries to a varying ex tent. In one autopsy study of 40 patients (Takemura et al . 1992), the degree of granulomat ous vascular involve- ment related to the degree of parenchymal granulomas, and venous invo lvement was more prominent than arterial involvement. Determining the mechanism of PH in pa tients without advanced fibrosis is often difficult without pathological examination of eit her large biopsies or autopsy specimens of explanted lungs. One series examined 22 patients with sarcoid and PH retrospectively (after exclusion of CTEPH). Fifteen had stage IV disea se and seven had no fibrosis but did have more ground glass attenuation on CT than the fibr otic group. Five of the fifteen with severe fibrosis underwent lung transplantation. Four o ut of five had evidence of vascular granulomas (predominantly venous, and arterial granulom as seen only in two). In addition, an occlusive venopathy was seen in all five patients wit h intimal fibrosis, recannalization, chronic haemosiderosis and iron deposits on elastic la minae, in the absence of any other cause of pulmonary venous hypertension. The possibility of CASE HISTORIES IN RESPIRATORY MEDICINE 144 more than one causal mechanism inducing PH in the same patient, therefore, makes attributin g degrees of causality difficult. Progress Unfortunately the patient collapsed and died at home before further investiga- tions were p erformed. Post-mortem examination revealed massive pulmonary thrombo-embolism and evidence of extensive thrombus in the right iliofemo- ral vein. Unfortunately no lung tissue was ret ained for further histological assessment. Further reading Nunes H , Humbert M , Capron F, Brauner M, Sitbon O, Battesti JP ( 2006 ). Pulmonary hypertension associated with sarcoidosis: mechanisms, haemodynamics and prognosis . Thorax ; 61 ( 1 ): 68 \200\223 73 . Shigemitsu H , Nagai S , Sharma OP ( 2007 ). Pulmonary hypertension and granulomatous vasculitis in sarcoidosis . Current Opinion in Pulmonary Medicine ; 13 : 434 \200\223 438 . Takemura T , Matsui Y , Saiki S , Mikami R ( 1992 ). Pulmonary vascular involvement in sa rcoidosis: a report of 40 autopsy cases . Human pathology ; 23 ( 11 ): 1216 \200\223 1223 . Case 18 A 48-year-old Caucasian woman presented to her general practitioner with dyspnoea on minima l exertion. She was wheezy on examination, peak flow was 210L/min (predicted = 470) and she was therefore diagnosed with asthma and started on inhaled 2 agonist and inhaled steroid . Despite this, she contin- ued to deteriorate, but responded well to a short course of ora l steroids. She was started on a combined high-dose steroid and long-acting 2 agonist inh aler, and provided with inhaler technique education. On review 1 month later, her peak flow s had stabilized at around 370L/min and an asthma treatment plan was drawn up with the pati ent. Four months later, she presented to the acute medical take with progressive deterioration o ver a 2-month period, requiring recurrent short courses of ster- oids from her GP. There wa s a 3-week history of productive cough, malaise and sweats. On examination, she was tachyca rdic, tachypnoeic and had widespread inspiratory crackles and cervical lymphadenopathy. SaO 2 on air was 90%. Investigations \227\206 Renal and liver function normal \227\206 CRP >180mg/L \227\206 Hb, 13.9g/dL, platelets, 672 \227 10 9 /L \227\206 White cell count, 27.9 \227 10 9 /L (eosinophils 15.4 \227 10 9 /L) \227\206 Urine dipstick n egative for blood/protein \227\206 CXR ( Fig. 18.1 ), HRCT ( Fig. 18.2 ). CASE HISTORIES IN RESPIRATORY MEDICINE 146 Fig. 18.1 CXR. CASE 18 147 Fig. 18.2 HRCT chest. Questions 18a) Describe the CXR. 18b) Provide a differential diagnosis for the CXR appearance. 18c) Provide a differential diagnosis for this case. 18d) Describe the HRCT images. 18e) What is the most likely diagnosis here and why? 18f) What investigations are indicated, and what is the management of this condition? CASE HISTORIES IN RESPIRATORY MEDICINE 148 Answers 18a) Describe the CXR. The CXR shows extensive patchy consolidation throughout the right lung field, small areas o f consolidation with multiple nodules in the left-upper zone, and more extensive patchy con solidation in the left-lower zone. In addition there is a mild thoracic scoliosis. 18b) Provide a differential diagnosis for the CXR appearance. The differential diagnosis of multifocal consolidation on the CXR includes the following: Common causes \227\206 Infection Bacterial pneumonia Pnuemocystis jirovecii pneumonia TB (usually reactivation of latent disease) Viral pneumonia (e.g. influenza) \200\224more commonly diffuse or multifocal \227\206 Neoplasm Lymphoma (usually associated with hilar and mediastinal lym- phadenopathy) Broncho-alveolar cell carcinoma (rarely associated with hilar and mediastinal lymphadenopathy) Multiple pulmonary metastases \227\206 Inflammatory/other Drug reactions (methotrexate, nitrofurantoin, amiodarone) Parasitic disease (migration of Ascaris and Strongyloides nematodes through the pulmonary vascular bed) Acute and chronic eosinophilic pneumonia Cryptogenic organizing pneumonia (COP) Uncommon causes \227\206 Fungal pneumonias (blastomycosis, coccidioidomycosis) \227\206 Melioidosis (consider in traveler to South East Asia) \227\206 Septic pulmonary emboli (e.g. staphylococcal bacteraemia) \227\206 Invasive aspergillosis (immunocompromised) CASE 18 149 \227\206 Sarcoidosis \227\206 Churg Strauss syndrome/Wegener \200\231s disease \227\206 Collagen vascular disease (SLE pneumonitis, mixed connective tis- sue disease) \227\206 Silicosis/pneumoconiosis (late stage). 18c) Provide a differential diagnosis for this case. Eosinophilic lung disease may be associated with peripheral blood eosi- nophilia, or infilt ration of the lung parenchyma with eosinophils with a normal peripheral count. Loeffler \200\231s syndrome (as in this case) is the association of lung infiltrates and a periphera l blood eosinophilia. The differential diagnosis for eosinophilic lung disease is as follow s: \227\206 Pulmonary eosinophilia Drug induced (e.g. nitrofurantoin, phenytoin) Acute eosinophilic pneumonia (AEP) Chronic eosinophilic pneumonia (CEP) Churg Strauss syndrome Allergic bronchopulmonary aspergillosis Asthma (usually mild eosinophilia) Parasitic infections: allergic reaction ( Ascaris, hookworm, Strongy- loides); parenchymal invasion (e.g. paragonomiasis); disseminated parasitic infection (e.g. schistosomiasis, Str ongyloides ); tropical pulmonary eosinophilia ( Wucheria bancrofti , Brugia malayi ) Other causes: idiopathic hypereosinophilic syndrome (HES); intersiti- tial lung disease; ne oplasia (including squamous cell lung carcinoma). 18d) Describe the HRCT images. The HRCT shows multifocal bilateral consolidation (with air broncho- grams) in the right-up per and lower lobes, and in the left-lower lobe. In addition, there is interlobar septal th ickening in the right lung ( Fig. 18.3 ). 18e) What is the most likely diagnosis here and why? The most likely diagnosis is chronic eosinophilic pneumonia (CEP), which presents with coug h, dyspnoea and systemic symptoms progress- ing over several months. Patients may experienc e chest pain, night sweats, myalgia and haemoptysis. A peripheral blood eosinophilia is see n in 70% of cases, and raised inflammatory markers and thromboc- tyosis are usual. The CXR reveals alveolar shadowing with the classical CASE HISTORIES IN RESPIRATORY MEDICINE 150 Fig. 18.3 Expanded HRCT chest. description of \200\230photographic negative of pulmonary oedema \200\231 (extensive bilat eral peripherally based consolidation) seen in around 25% of cases. Asthma is associated (e ither before or after the initial presentation) in over 50%. Alternative possibilities incl ude: \227\206 Acute eosinophilic pneumonia (AEP) is characterized by an acute illness (normally less than 7 days duration) associated with cough, dyspnoea, malaise, fevers and pleuritic chest pain. CXR reveals subtle interstitial infiltrates early in the disease, which may pro gress to florid consolidation that is not peripherally based. Small pleural effusions are c ommon; peripheral blood eosinophilia is uncommon. \227\206 There is no travel history to suggest helminth disease \227\206 Although severe bilateral bacterial pneumonia or COP may produce this radiologica l pattern, a shorter history and more severe illness would be expected in bacterial pneumon ia, and the typical \200\230migratory \200\231 pattern of COP is not demonstrated. In addi tion, such high peripheral eosinophil count is not expected in these conditions (and eosino pae- nia is expected during any systemic infection). \227\206 The absence of evidence of systemic vasculitis (upper respiratory tract, skin, pe ripheral nerves, heart, gut) makes Churg Strauss syndrome less likely. \227\206 Allergic bronchopulmonary aspergillosis is usually associated with central bronchiectasis and perihilar shadowing. CASE 18 151 \227\206 In idiopathic hypereosinophilic syndrome (HES), a high peripheral blood eosinophi lia (>1500/ l) for more than 6 months in the absence of identifiable cause is required for diagnosis, in association with organ involvement. Patients present with a chronic progress ive sys- temic illness with weight loss, cachexia, pruritis and cough. Lung infil- trates a re seen in up to one-third of cases, with the major morbidity and mortality associated with cardiac complications. 18f) What investigations are indicated, and what is the management of this condition? Investigations: \227\206 Authorities differ as to the level of investigation required to establish a diagn osis, with some suggesting lung biopsy as mandatory, while oth- ers suggest BAL is sufficie nt to exclude other diagnoses in association with a typical radiological pattern. \227\206 BAL >40% eosinophils seen in CEP (>25% in AEP), excludes invasive helminth or fun gal disease. In a case with convincing radiological and clinical features such as this, thi s may not be required. \227\206 Lung biopsy may be undertaken where there is diagnostic doubt (characteristic his tological features: interstitial and alveolar eosinophil infiltration, multinucleate giant cells, bronchiolitis obliterans with organizing pneumonia). \227\206 Consider ANCA if Churg Strauss is a possibility, due to associated vasculitis (bu t p-ANCA positive in only 50% of Churg Strauss cases) \227\206 IgE levels (>1000ng/mL), Aspergillus precipitins, aspergillus skin test if ABPA considered. Management: \227\206 Spontaneous recovery in CEP is rare (<10%), and continued illness may result in c hronic respiratory impairment with irreversible fibrosis; therefore, prompt therapy is indi cated once diagnosis is established. \227\206 Oral steroid (prednisolone 40 \200\22360mg/day) titrated to eosinophil count (loo king for total suppression) \200\224CEP is highly sensitive to steroid treatment, and lack of response to steroid therapy should prompt reconsideration of the diagnosis. \227\206 There are no randomized trials of therapy in CEP, but most authorities recommend continuation of high-dose therapy until, or for some weeks after, complete symptomatic and radiological resolution (4 \200\2236 weeks). Steroid dose should then be halved for 2 month s. CASE HISTORIES IN RESPIRATORY MEDICINE 152 \227\206 Total treatment course is recommended for between 3 and 9 months, as relapses are common. Dose should be tapered slowly, guided by clinical features, lung function and eosi nophil count. Consideration should be given to bone protection therapy (calcium, vitamin D and a bisphosphonate) as long-term treatment is likely. \227\206 In patients in whom decreasing steroid dose proves challenging, consid- eration s hould be given to alternate day regimens and steroid-sparing agents. There are case reports of success with high-dose, inhaled ster- oid, in addition to the lowest possible dose of o ral prednisolone. \227\206 In the case of disease relapse off therapy, steroid treatment should be re-initia ted as above. The disease tends to respond well even after relapse. However, steroid therap y may be required for years, and some patients end up on permanent steroid therapy. The maj ority of patients ( ) require more than 19 months of therapy and some patients may require life-long therapy. \227\206 In patients in whom deterioration occurs, evolution into Churg Strauss syndrome should be considered. Progress ANCA was negative. Bronchoalveolar lavage and transbronchial biopsies revealed evidence of eosinophilic pneumonia. The patient was commenced on prednisolone 30mg daily for 2 months, at which point slow tapering of the dose was attempted. Ten months later she was maintained on 10mg pred- nisolone per day with a normal eosinophil count, no symptoms and a normal ch est radiograph. Rheumatological review suggested no evidence of vasculitis. Further reading Marchand E , Cordier JF ( 2006 ). Idiopathic chronic eosinophilic pneumonia . Semin Respir Crit Care Med ; 27 ( 2 ): 134 \200\223 141 . Case 19 Case A A 48-year-old woman presented to the respiratory sleep clinic with a com- plaint of general non-specific tiredness, excessive sleepiness, and snoring. Her Epworth sleepiness score (E SS) was 17/24 (upper limit of normal = 9). A rou- tine sleep history revealed no obvious ca use for the sleepiness, although she was currently seeing a counselor for depression. Sleep study was normal, apart from approximately 30 minutes of snoring. A diagnosis of depressio n-induced sleepiness and tiredness was made. Two months later, she complained of altered vision in the temporal field of her right eye. An optician found an incomplete right superior temporal quadrantinopia. An MRI was performed ( Fig. 19.1 ). Fig. 19.1 Brain MRI. CASE HISTORIES IN RESPIRATORY MEDICINE 154 Case B A 40-year-old women was referred to the sleep clinic with an unusually rapid onset of sleep iness over 6 weeks. There were no features in the history, or on the sleep study, to sugges t sleep apnoea, narcolepsy, periodic limb movements during sleep, poor sleep hygiene or dep ression. When alert, she was fully conscious and orientated. A brain CT with contrast was performed ( Fig. 19.2 ). Fig. 19.2 Brain CT. CASE 19 155 Questions 19a) What does the MRI on case A show? 19b) How could the lesion in the case A have been responsible for the earlier symptoms of tiredness and sleepiness? 19c) What does the CT show on case B? 19d) How could the lesions in case B have been responsible for the sleepiness? CASE HISTORIES IN RESPIRATORY MEDICINE 156 Answers 19a) What does the MRI on case A show? The MRI of case A shows a cystic lesion arising from, and expanding, the pituitary fossa wi th a significant suprasella extension. The chiasma and hypothalamus are significantly compr essed. The appearances are of a Rathke \200\231s cleft (or pouch) cyst, a type of craniopha ryngioma ( Fig. 19.3 ). Position of optic chiasma Hypothalamus Suprasella extension Cyst in pituitary fossa Fig. 19.3 MRI, midline coronal section showing enlarged pituitary fossa. 19b) How could the lesion in the case A have been responsible for the earlier symptoms of tiredness and sleepiness? This lesion might be causing the symptoms in two ways: 1. Pituitary function may be compromised with a consequent low cortisol. This patient had an entirely normal endocrine profile. 2. Compression of the hypothalamus and suprachiasmatic nucleus. The hypothalamus contains a reas that control alertness/sleepiness and the supra chiasmatic nucleus is involved in cont rolling circadian rhythms. Craniopharyngiomas are rare, usually suprasellar, and are either solid, cystic or mixed, be nign tumors arising from remnants of Rathke \200\231s pouch along a line from the nasophary nx to the third ventricle. They are also known as Rathke \200\231s pouch tumors, hypophysea l duct tumors, or adamantinomas, depending on their histological type. They usually occur b efore age 20, or after age 40. Sleepiness following surgical resection of, or radiotherapy to, crani- opharyngiomas is als o well-recognized, and is likely to be due to hypoth- alamic damage or altered levels of ne urotransmitters (although secondary hormonal abnormalities do not seem to be the explanatio n). CASE 19 157 19c) What does the CT show on case B? The upper CT from case B (Fig. 19.2) shows a large enhancing, space- occupying lesion in th e left-frontal lobe (with extensive surrounding oedema and midline shift). There is another enhancing lesion in the hypothalamus (center of lower image, Fig. 19.2). 19d) How could the lesions in case B have been responsible for the sleepiness? Again, involvement of the hypothalamus will also interfere with its func- tion and potentia lly cause sleepiness. Progress In case A, surgical resection of the Rathke \200\231s cyst lead to resolution of the sleepi - ness, the Epworth sleepiness score falling to 9. In case B, left-frontal lobe biopsy reve aled a B cell lymphoma; steroids, then radio-therapy, produced resolution of sleepiness and the patient is well 17 years later. It is important in the sleep clinic to consider other diagnoses of excessive daytime sleepi ness, apart from the common ones, such as sleep apnoea, poor sleep hygiene and depression. The following is a limited list of non-respiratory causes of sleepiness that may be encount ered by those running a sleep clinic. More common \227\206 Depression, often missed \227\206 Lifestyle issues/poor sleep hygiene \200\224alcohol, late-night working, shift work, caffeine abuse, family circumstances, etc. \227\206 Drugs \200\224some of the anti-hypertensives (e.g. blockers) and psychoac- tiv e drugs (e.g. anti-depressants and anxiolytics) can provoke sleepiness \227\206 Narcolepsy \200\224variable combination of cataplexy (sudden loss of mus- cle ton e in response to excitement or anticipation), sleep paralysis (frightening paralysis on wak ening for a few seconds or minutes) and prolific vivid dreaming, often at sleep onset \227\206 Periodic limb movements during sleep (associated with restless legs during the da y, especially in renal failure, and can be provoked by the SSRI anti-depressants) \227\206 Simply being at the sleepier end of the normal spectrum. Less common \227\206 Hypothalamic damage (e.g. post-severe head injury, cranial irradia- tion or space-occupying lesion) CASE HISTORIES IN RESPIRATORY MEDICINE 158 \227\206 Post-infectious (e.g. Epstein \200\223Barr virus) \227\206 Idiopathic hypersomnolence (sometimes hereditary) \227\206 Certain neurological disorders, such as myotonic dystrophy, Parkinson \200\231s and previous stroke \227\206 The symptom may really be tiredness, such as in \200\230ME \200\231 or insomnia, when the ESS is usually low, as this scale measures sleepiness rather than tiredness \227\206 Insomnia/sleepiness in blind people with no retinal function \200\224a cir- cadia n problem where the 24-h cycle is not linked with the real world through light and melatoni n production. Further reading Chapman S, Robinson G, Stradling J, West S. ( 2009 ) Sleep and ventilation . Oxford Handbook of Respiratory Medicine ( 2 nd edn), chapter 14 , pp. 85 \200\22389 . Case 20 A 58-year-old man was referred with a fever up to 38 \232C associated with hepa- titis, per sisting despite several antibiotic courses. Investigations showed mod- estly elevated infla mmatory markers (CRP, 75mg/L), a CXR showed pulmonary infiltrates, several sets of blood cu ltures, viral hepatitic screens and a myeloma screen were negative. Bronchoscopy was non-di agnostic. A liver biopsy showed caseating granulomas. His previous medical history included hypertension, prostatism and superficial transitional cell carcinoma of the bladder, treat ed with intravesical BCG (bacillus Calmette-Gu rin) 8 months previously. Question 20a) This patient \200\231s current presentation and urological history are related. Suggest an underlying diagnosis. 20b) How has the condition been acquired? 20c) What other clinical presentations are recognized? CASE HISTORIES IN RESPIRATORY MEDICINE 160 Answers 20a) This patient \200\231s current presentation and urological history are related. Suggest an underlying diagnosis. The underlying diagnosis is disseminated Mycobacterium bov is . 20b) How has the condition been acquired? M. bovis has been acquired through intra-vesical BCG. BCG consists of live attenuated M. bo vis . The mechanism of action of intra-vesical BCG is complex; it acts as a non-specific st imulant of the immune system by inducing granulomatous inflammation. Anti-tumor activity is concen- trated at the site of BCG administration, hence topical application is used. Altho ugh virulence is markedly reduced, rarely it may cause infec- tion or even dissemination af ter intra-vesical administration (1 of 200 in one case series) or BCG vaccination. Immunosu pressed patients are much more susceptible to this. Intra-vesical BCG is widely used in the management of bladder cancer. 20c) What other clinical presentations are recognized? Clinical presentation of Mycobacterium bovis infection. Symptoms can present within hours o r up to years after intra-vesical BCG treatment. Clinical presentations include miliary pne umonitis, granulomatous hepatitis, soft tissue infections, bone marrow involvement and seps is. Disseminated Mycobacterium bovis is a potentially life-threatening com- plication, and so clinicians must remain vigilant regarding its possibility even months or years after tre atment. CASE 20 161 Question 20d) Suggest other potential causes of fever post-intra-vesical BCG. 20e) What are the principles of treatment of Mycobacterium bovis ? 20f) How are M ycobacterium bovis and M ycobacterium tuberculosis distin- guished histologically and microbiologically? CASE HISTORIES IN RESPIRATORY MEDICINE 162 Answers 20d) Suggest other potential causes of fever post-intra-vesical BCG. The differential diagnosis of fever occurring post-intra-vesical BCG includes secondary Gra m-negative sepsis and a hypersensitivity reaction. A much commoner side-effect of intra-ves ical BCG is cystitis. 20e) What are the principles of treatment of Mycobacterium bovis ? If a patient is acutely unwell, and Mycobacterium bovis is suspected, as in this case, empi rical therapy should be started before culture results are available. Choice of antibiotics for Mycobacterium bovis is similar to that for Mycobacterium tuberculosis ; however, drug resistance is much com- moner, in particular to pyrazinamide. In view of drug resistance, a longer duration of treatment of 9 \200\22312 months of all drugs, including at least rifam picin and isoniazid, is usually given. The patient had Mycobacterium bovis resistant to pyr azinamide and with intermediate resistance to iso- niazid. He was treated with rifampicin, isoniazid, ethambutol and moxi- floxacin for one year. 20f) How are Mycobacterium bovis and Mycobacterium tuberculosis distin- guished histologically a nd microbiologically? Mycobacterium bovis may cause caseating or non-caseating granulomas, whereas Mycobacterium tuberculosis usually causes caseating granulo- mas. Otherwise they are indistinguishable cl inically or pathologically. Differentiation is only achieved following culture, and is sugg ested by the typical resistance pattern of Mycobacterium bovis to pyrazinamide. Further case of Mycobacterium bovis A retired agriculture lecturer had a lower respiratory tract infection that failed to respo nd to several courses of empirical antibiotics. His past medical history was of Crohn \200 \231s disease, diagnosed 20 years previously. He had undergone a colectomy for refractory c olonic and peri-anal disease. Colonic histology showed granulomas, initially thought to be non-caseating, supporting the diagnosis of Crohn \200\231s disease. Given the failure of his lower respiratory tract infection to resolve, he under- went bronc hoscopy, and was found to have Mycobacterium bovis infection. This led to re-examination of bowel histology from 20 years ago. In retrospect it was observed to show caseating granulo ma, which would be consistent with a diagnosis of Mycobacterium bovis rather than Crohn \200\231s disease. CASE 20 163 Question 20g) How might this man have acquired Mycobacterium bovis ? 20h) What public health measures have led to reduced incidence of Mycobacterium bovis in the UK? CASE HISTORIES IN RESPIRATORY MEDICINE 164 Answers 20g) How might this man have acquired Mycobacterium bovis? The source of infection is not known for certain in this case; however, Mycobacterium bovis is a zoonosis that may infect humans, along with a broad range of domestic and wild mammal s. Historically the common- est source has been from inhalation or ingestion of unpasteuriz ed milk, which may have been the source in this case. Person-to-person transmis- sion of My cobacterium bovis is very rare. 20h) What public health measures have led to reduced incidence of Mycobacterium bovis in the UK? Public health measures to reduce incidence of Mycobacterium bovis in the UK. Zoonotic TB wa s formerly an endemic disease in the UK due to consumption of raw cow \200\231s milk, with badgers helping to spread infection between herds of cattle. This has largely been eradicat ed by pasteurization of milk, and systematic culling of cattle reacting to compulsory tuber culin tests. Today most cases of zoonotic TB diagnosed in the UK are attributable to reacti vation of long-standing latent infections acquired before wide- spread adoption of milk pas teurization, or Mycobacterium bovis infections contracted abroad. Further reading De la Rua-Domenech R ( 2006 ). Human Mycobacterium bovis infection in the United Kingdom: I ncidence, risks, control measures and review of the zoonotic aspects of bovine tuberculosis . Tuberculosis ; 86 : 77 \200\223 109 . Paterson DL , Patel A ( 1998 ). Bacillus Calmette-Guerin (BCG) immunotherapy for bladder ca ncer: review of complications and their treatment . Aust N Z J Surg ; 68 ( 5 ): 340 \200 \223 344 . Prescott S , Jackson AM , Hawkyard SJ , Alexandroff AB , James K ( 2000 ). Mechanisms of action of intra-vesical BCG . Clin infection Dis ; 31 suppl 3 : S91 \200\223 93 . Thoen C , LoBue P , de Kantor I ( 2006 ). The importance of M bovis as a zoonosis . Vetinar y Microbiology ; 112 : 339 \200\223 345 . Case 21 A 52-year-old man with several years of snoring was referred for assessment of possible obs tructive sleep apnoea. His wife described characteristic obstructive apnoeas during the nig ht, increasingly frequent over the last year. The snoring had become so bothersome for the patient \200\231s wife that they often slept in sepa- rate rooms. The patient awoke feeling refreshed and did not complain of feel- ing sleepy during the day. He denied sleepiness on prolonged drives, was able to concentrate on reading a book and could watch TV for an hour or so in the evening without falling asleep. He had worked as a commercial airline pilot f or the last 15 years and sleepiness had never interfered with his work. He had been success fully treated for essential hypertension for 12 years with bendrofluazide. On examination t he patient had retrognathia, a collar size of 16 inches, BMI 25, normal nasal patency and n o appreciable abnormality of the orophar- ynx. Completion of the Epworth sleepiness score ( with wife present and agreeing with his account) gave a score of 3/24 (upper limit of norma l, 9). A sleep study ( Fig. 21.1 ) demonstrated severe obstructive sleep apnoea with an oxy gen desat- uration index (ODI >4% desaturations) of 58/h. Start Time + Date: 22:23:33 27/03/2006 Y-axis from 70% to 100% Start of night 100 70 End of night Fig. 21.1 Eight sequential hours of oximetry taken from the sleep study. This page intentionally left blank CASE 21 167 Questions 21a) What treatment would you recommend for this patient? 21b) Would you undertake any further investigations? 21c) What advice would you give to this patient about driving? 21d) What impact will the diagnosis have on continuing employment as an airline pilot for this patient? CASE HISTORIES IN RESPIRATORY MEDICINE 168 Answers 21a) What treatment would you recommend for this patient? Although severe OSA was identified on sleep study, he does not complain of excessive daytim e sleepiness and therefore does not have obstructive sleep apnoea syndrome. This distinctio n is important when deciding upon appropriate treatment, and when providing advice regardin g driving (see answer 21c) and so on. In the absence of excessive sleepiness, as long as there is no reason to think the patient is under-estimating this (corroborative history from partner is invaluable), there is littl e justification for recommending nasal CPAP. The principle reason for instituting CPAP in O SA is for the treat- ment of excessive daytime sleepiness. There is no convincing evidence that treatment with CPAP improves blood pressure control in non-sleepy patients with OSA, o r indeed long-term morbidity or mortality. The patient (and his wife) are principally compl aining of snoring and in the first instance careful enquiry as to potential aggravating fac tors (e.g. smoking, alcohol) should be undertaken. A jaw advancement device may be helpful in improving symptoms of snoring. The patient must be counseled strongly that, if there is any concern about excessive daytim e somnolence in the future, he must be re-assessed. 21b) Would you undertake any further investigations? Further investigation in these circumstances would really depend on your belief as to the p atient \200\231s true level of sleepiness, and whether you would wish to confirm this. Ther e is not a good correlation between severity of OSA and level of sleepiness, but his OSA is severe and the Epworth sleepiness score may be purposely under-estimated if the patient (a nd their partner) fears he will lose his livelihood. In cases where either you do not belie ve the reported level of sleepiness, or you feel the patient needs convincing of their true level of sleepiness, a wakefulness test can help. These tests do not correlate with object ive measures of severity of OSA (e.g. Apnoea-hypopnoea Index or ODI), or with future likeli hood of a driving accident. In this case, however, because of his job as a pilot, objective clarification of his reported lack of sleepiness is recommended (see answer 21d). Level of sleepiness can be more objectively defined by: \227\206 Maintenance of wakefulness test (MWT). The patient is asked to stay awake lying s emi-recumbent for 40 minutes in a quiet and darkened CASE 21 169 room on four occasions throughout the same day at 2-hourly intervals (again with continuous EEG monitoring) and length of time taken to fall asleep is recorded. \227\206 Oxford sleep resistance test (OSLER). A variant of the MWT, except sleep latency is assessed behaviourally without EEG monitoring (and without a technician engaged in conti nuous monitoring of the EEG) and is, therefore, easier to administer. The patient is left s emi-recumbent in a quiet and darkened room for 40 minutes, and is asked to stay awake and p ress a fingerpad in response to a dim light, lit regularly for 1 second in every 3. The num ber of missed responses is recorded, and persistent lack of response (failure to respond fo r 21 seconds, or 7 illuminations) defines sleep onset, recorded by computer. \227\206 Multiple sleep latency test (MSLT). Conversely to the MWT, patients lie in a quie t, dim room and are asked to fall asleep (defined by EEG monitoring) on four or five occasi ons at 2-hourly intervals throughout the day and the time taken to do so is measured. 21c) What advice would you give to this patient about driving? When considering driving, the over-riding principle, from a legal point of view, is that an y patient who drives must take responsibility for being safe to drive. Any driver who falls asleep while driving and causes an accident involving themselves or others is personally l iable and, in the case of fatal incidents, may be charged with causing death by dangerous d riving, potentially receiving a jail sentence. Patients with obstructive sleep apnoea syndr ome must inform the DVLA of their diagnosis and not drive until established on treatment th at has improved their exces- sive daytime sleepiness (see case 15). This patient, however, is adamant he is not sleepy and, therefore, does not need to inform the DVLA of his OSA dia gnosis, as he does not have the syndrome. As long as he remains free of sleepiness, he can drive, but must be counseled strongly that, if the situation changes, he must not drive and be referred for re-assessment. All such patients should be advised not to drive if at all sleepy. 21d) What impact will the diagnosis have on continuing employment as an airline pilot for this patient? He must inform his airline and the Civil Aviation Authority (CAA) of the diagnosis of OSA, but emphasize he does not have OSA syndrome. As with the driving rules, there should be no impact on his continuing to fly, but the CAA will require confirmation of lack of sleepines s by an CASE HISTORIES IN RESPIRATORY MEDICINE 170 objective measure. The same advice applies about needing re-assessment if sleepiness become s a problem. Were the situation different and sleepiness was a problem, a minimum of 6 weeks CPAP treatm ent, accompanied by improved sleepiness (ESS \211 9), is required before the CAA would all ow such a pilot to fly. If there is any doubt then as to the genuine level of sleepiness, a MSLT is advised in cur- rent CAA guidelines, despite its poor ability to predict real life sleepiness and lapses in performance. Further reading http://www.caa.co.uk/docs/49/SRG_MedSleepApnoea.pdf (accessed 1st September 2009) Bennett L S , Stradling JR , Davies RJO ( 1997 ). A behavioral test to assess daytime sleepiness in obstructive sleep apnoea . J Sleep Res ; 6 : 142 \200\223 145 . Stradling JR ( 2008 ). Driving and obstructive sleep apnoea . Thorax ; 63 : 481 \200\223 4 83 . Case 22 A 68-year-old man presented with 2 months of progressive breathlessness on exer- tion and w eight loss of 7kg. He had a past medical history of an anterior myocar- dial infarction 3 m onths previously, and hypertension. He was a retired plumber and had had definite asbestos exposure in the past. He had never smoked. On examination he had an oxygen saturation of 95% on air. There was dullness