Case B Ultrasound was suggestive of a mass lesion rather than septated fluid in the area abutting the pericardium. The patient underwent VATs, which revealed a cystic mass lesion. Multiple biopsies were taken, and the septated effusion cleared. Biopsies revealed abnormal cells wi th spindle cell morphology, con- sistent with a sarcoma. He went on to receive chemotherapy , and died 7 months later. Case 7 A 32-year-old American woman was referred for investigation of left-sided subcostal pleurit ic chest pain. Four months earlier she had been treated for left lower lobe pneumonia (radi ologically confirmed) requiring two courses of antibiotics (amoxicillin and erythromycin). After this illness the chest pain persisted, and she felt \200\230tired and drained \200 \231. She also reported an intermittent cough, productive of small amounts of \200\230off- white \200\231 sputum, but denied other respiratory symptoms. She had had no haemoptysis, f evers or sweats, anorexia or weight loss. She had a history of a left-sided pneumonia aged 8, and of being \200\230chesty \200\231 until 13; otherwise she had been well. She had nev er smoked, and sel- dom drank alcohol. There were no abnormal physical signs. Her CXRs are shown in Fig. 7.1a and b . Questions 7a) What do the CXRs show? 7b) List potential causes for the ongoing symptoms? 7c) What investigation would you like to do next? CASE 7 45 (a) (b) Fig. 7.1 (a) PA and (b) lateral CXR on presentation. CASE HISTORIES IN RESPIRATORY MEDICINE 46 Answers 7a) What do the CXRs show? Consolidation is seen within the postero-basal segment of the left lower lobe (retro-cardia c opacification) on both the PA and lateral images (see Fig. 7.2 ). Fig. 7.2 Lateral CXR: retro-cardiac area of consolidation circled. 7b) List potential causes for the ongoing symptoms? Potential causes for this patient \200\231s ongoing pleuritic chest pain, intermittent prod uctive cough and radiological non-resolution could be: Common: \227\206 Infection Post-infectious pleurisy usually recedes quickly with antibiotic therapy supplemented with appropriate analgesia. Prolonged post- infective cough is common (especially with viral aet iologies) and can last for months. Ongoing symptoms and non-radiological resolution, following standard anti-microbial therapy , should raise suspicion of atypical pathogens, e.g. Legionella spp., Mycoplasma , Chlamydi a pneumoniae , fungi or mycobacteria \227\206 Malignancy CASE 7 47 \227\206 Suppurative lung disease Underlying bronchiectasis or a lung abscess should be consid- ered although the radiologica l appearances are not typical for the latter. Less common: \227\206 Recurrent gastric aspiration \227\206 Thromboembolic disease (with resultant infarction accounting for the radiological change) \227\206 Cryptogenic organizing pneumonia (COP) \227\206 Eosinophilic lung disease, e.g. eosinophilic pneumonia or allergic bronchopulmona ry aspergillosis (ABPA, usually upper lobe predominant) \227\206 Vasculitis/collagen vascular disease, such as Wegener \200\231s granulomatosis or rheumatoid arthritis \227\206 Congenital abnormality, e.g. bronchogenic cyst, bronchopulmonary sequestration \227\206 Drug-induced lung disease. 7c) What investigation would you like to do next? Contrast-enhanced thoracic CT would be a suitable next investigation in view of the failure of clinical improvement and lack of radiological resolu- tion 8 weeks following appropriat e therapy. Further information She had no history of chronic chest disease, tuberculosis, collagen vascular disease, radia tion exposure, foreign body inhalation or risk factors for acquired immunodeficiency states . Investigations \227\206 Hb 15.2g/dL, MCV 86.5fL, WCC 9.2 \227 10 9 /L (normal differential), platelets 387 \227 10 9 /L \227\206 U&E, LFT, glucose, TFT all normal \227\206 CRP <8mg/L, ESR 10mm/h \227\206 Immunoglobulins, normal \227\206 Antinuclear antibodies and rheumatoid factor, negative CASE HISTORIES IN RESPIRATORY MEDICINE 48 \227\206 Streptococcus pneumoniae and Haemophilus influenzae antibody responses within the normal range \227\206 Sputum culture, no growth \227\206 Full pulmonary function tests, normal. \227\206 Contrast enhanced thoracic CT scan (Fig. 7.3). (a) (b) Fig. 7.3 (a) and (b) Contrast-enhanced CT chest images. CASE 7 49 Questions 7d) What does the CT scan demonstrate? 7e) What is the diagnosis? 7f) What are the treatment options? CASE HISTORIES IN RESPIRATORY MEDICINE 50 Answers 7d) What does the CT scan demonstrate? The magnified CT image in Fig. 7.4a demonstrates heterogeneous consolidation within the lef t base sharing an irregular border with the neighboring lung parenchyma. Cystic components are evident and an anomalous vessel is present within the mass (arrow). In the CT ( Fig. 7.4b ), this vessel can be seen as it originates from the aorta (arrow) an d (images not shown) leads directly into the lesion. The lungs are otherwise normal. (a) (b) Fig. 7.4 (a), (b) 7e) What is the diagnosis? These findings are in keeping with a diagnosis of intralobar sequestration (ILS). Pulmonary sequestration is rare and accounts for 0.15 \200\2236.4% of all congenital pulmon ary malformations. It is characterized by the presence of a segment of lung that has no ide ntifiable contact with the normal bronchial tree and derives its blood supply from an anoma lous systemic artery. Two types are recognized: intralobar (ILS) and extralobar seques- tra tion (ELS). Table 7.1 summarizes the main clinical differences. \227\206 Other congenital anomalies (e.g. diaphragmatic hernias, congenital cystic adenoma toid malformation type (CCAM) II and cardiopulmo- nary disease) are seen in 10 \200\22314% of those with intralobar and 50% of those with extralobar sequestration. \227\206 The exact etiology of pulmonary sequestration is unknown. Development of ELS from an accessory lung bud, which arises cau- dally from primitive foreg ut, is postulated. It is theorized that this CASE 7 51 Table 7.1 Intralobar sequestration Extralobar sequestration Frequency 75% 25% Appearance Within visceral pleura of the normal lung Enclosed in a separate pleural sac Sex ratio 1M:1F 4M:1F Site 98% lower lobe 60% left-sided 95% left-sided 75% within costophrenic angle 10 \200\22315% sub-diaphragmatic Presentation Rare <2 years, often history of recurrent pneumonia in adulthood 61% at <6 months Asymptomatic cases (incidental finding) 15% 10% segment retains splanchnic (systemic) blood supply generating trac- tion on the lung fragme nt, which subsequently segregates from the main lung mass. The origin of ILS is contentious. The \200\230congenital \200\231 hypothesis mirrors that of ELS formation, whereas in the \200\230acquired \200\231 theory, ILS arises from transfo rmation of chronically inflamed normal lung (pseu- dosequestration), i.e. the presence of a n obstructed bronchus (medi- ated by inflammation, aspiration or infection) causing seconda ry occlusion of the local pulmonary artery supply leading to systemic arterial parasitisati on with vessel incorporation into the, now seques- tered, pulmonary tissue. \227\206 Patients often present with cough +/ \200\223 sputum production, recurrent pneumo nia or features secondary to related anomalies. Superimposed infections, i.e. fungal, tuber culosis, massive haemoptysis, haemothorax and cardiovascular complications can occur. Benig n and malignant tumors have been reported arising in sequestered lung. \227\206 Chest radiography typically shows lower lobe homogeneous consolida- tion or a mass. Cavitation and cystic areas may occur. \227\206 CT allows further definition of areas of sequestration. ILS characteristi- cally manifests as a homogeneous or heterogeneous mass sharing an irregular border with adjacent lung. Cavities may be seen and cysts with air-fluid levels present. The aberrant vessel sup plying the lesion is visualized in up to 80% of cases. Other associated anomalies may be no ted. CASE HISTORIES IN RESPIRATORY MEDICINE 52 \227\206 Conventional angiography has been the gold standard for abnormal vascular connect ions however non-invasive CT angiography and mag- netic resonance angiography are now super seding its use. 7f) What are the treatment options? Treatment options: \227\206 Symptomatic pulmonary sequestration: surgical resection, once infection has subsi ded, is recommended and can usually be performed thoracoscopically (VATs) Lobectomy is commonly performed for ILS Sequestrectomy for ELS cases is the usual approach \227\206 Pre-operative identification of aberrant vessels is helpful but is not a pre-requisite of successful surgery \227\206 The management of asymptomatic pulmonary sequestration is contro- versial, with s ome advocating routine resection and others opting for a conservative non-operative approac h. Prognosis is good, and resection of the abnormal segment is usually curative. Any mortality often reflects the presence of accompanying anomalies. Progress The patient remained well with only occasional low grade left-sided chest pain. She opted a gainst surgical resection, but was advised to take antibiotics promptly if she developed in fective symptoms. Further reading Corbett HJ , Humphrey GME ( 2004 ). Pulmonary sequestration . Pediatric Respiratory Reviews ; 5 : 59 \200\223 68 . Frazier AA , Rosado de Christenson MI , Stoker JT , Templeton PA ( 1997 ). Intralobar seque stration: radiologic-pathologic correlation . Radiographics ; 17 : 725 \200\223 745 . This page intentionally left blank CASE HISTORIES IN RESPIRATORY MEDICINE 54 Case 8 A 40-year-old accountant, recently moved into the area, presented with a 3-month history of cough and, over the previous month, dyspnoea on exercise. Initially antibiotics seemed to help, although repeated sputum cultures were negative. Whilst skiing at 3000m, he developed severe dyspnoea, which greatly curtailed his physical activity. On his return he also noti ced some dyspnoea during his usual exercise of cycling and circuit training. He had no relevant past medical history, apart from mild hayfever as a teenager. He had nev er smoked, drank six units of alcohol a week, and had no pets. He was married, heterosexual , with only one partner for many years. There was no history of reflux, sinusitis or wheeze . On examination On auscultation there were obvious fine bi-basal end-inspiratory crackles. His resting arte rial oxygen saturation was 97% on air, but fell to 93% after 30 steps up and down a 9in-hig h block. Investigations \227\206 CXR, equivocal diffuse shadowing throughout \227\206 FBC, U&Es and liver function tests were all normal \227\206 ANA/ANCA, negative; rheumatoid factor, 1/80; ESR, 14mm/h; CRP, 60mg/L \227\206 Serology, Q fever, psittacosis, mycoplasma, influenza A&B, legionella: all negative \227\206 Proteins and electrophoresis, IgG 22.5g/L (upper limit 13.0g/L), other- wise normal \227\206 Budgerigar, pigeon and hen precipitins, negative \227\206 Pulmonary function, Table 8.1. Table 8.1 Pulmonary function tests Measured Predicted FEV1(L) 3.2 3.3 VC (L) 3.7 4.0 FEV1/VC% 86 75 \200\22385% VA(L) 5.5 5.9 TLCO(mmol/min/kPa) 7.6 9.2 KCO(mmol/min/kPa/L) 1.39 1.70 CASE 8 55 Questions 8a) Suggest the two most likely diagnostic categories. 8b) Would you expect this drop of 4% SaO 2 on exercise in a normal person? 8c) Are the lung function results abnormal? 8d) What would be the most useful next investigation? CASE HISTORIES IN RESPIRATORY MEDICINE 56 Answers 8a) Suggest the two most likely diagnostic categories. The raised CRP, raised IgG and initial response to antibiotics, would suggest possible infe ction , but the history is a little long for this to be the likely explanation of all the s ymptoms. The CXR may indicate a viral infection, but is more likely to be due to a diffuse interstitial pneumonitis. The presence of crackles virtually rules out sarcoidosis, but sti ll leaves a wide differential. 8b) Would you expect this drop of 4% SaO2 on exercise in a normal person? The SaO 2 should not drop, even on heavy exercise, with a normal heart and lungs at sea lev el. A drop from 97% to 93% is equivalent to a fall in PaO2 of 3.3kPa, and is clearly abnorm al. However, it is important to do this test properly. Oximeters work by measuring the two relevant wavelengths (registering oxygenated and total hemoglobin) in pulsatile blood only, hence responding only to arterial blood and disregarding non-pulsatile capillary and venou s blood. If the hand is moving during the exercise, this can make the venous blood pulsate, thus fooling the oximeter into register- ing venous as well as arterial blood (particularl y if the cardiac output is low) and giving a falsely low value. Thus the reading is best ta ken when the patient has sat down after exercise, and the hand has been still for 15 \200 \22330 seconds (this is well before the SaO 2 begins to recover after exercise). 8c) Are the lung function results abnormal? The lung function is technically within the normal range but, given the overall scenario, t he fact that the gas transfer is towards the bottom end of normal in a previously fit indiv idual is supportive of interstitial lung disease. 8d) What would be the most useful next investgation? A high resolution CT scan (HRCT) will be the next most useful test, dif- ferentiating betwe en many of the different interstitial lung diseases. CASE 8 57 Fig. 8.1 Single HRCT slice at the level of the aortic arch. Questions 8e) What does the HRCT slice in Fig. 8.1 show? 8f) What should be done next to try and make a diagnosis? CASE HISTORIES IN RESPIRATORY MEDICINE 58 Answers 8e) What does the HRCT slice in Fig. 8.1 show? The HRCT appearances are typical of hypersensitivity pneumonitis (or extrinsic allergic alv eolitis, Fig. 8.2a). Multiple poorly-defined nodules are seen centered around the middle of the secondary pulmonary lobule (Fig. 8.2b), centrilobar or peribronchial (i.e. at the bron chovascular bun- dle where the main antibody/antigen reaction occurs). 8f) What should be done next to try and make a diagnosis? The history should be revisited \200\224was exposure to a relevant allergen missed? Lung bi opsy could be considered for histological confirmation. Lobar pulmonary artery Pulmonary veins and lymphatics Lobar bronchiole Central bronchovacular core 1 cm Acinus Visceral pleural surface Interlobar septum (a) (b) Fig. 8.2 (a) Actual and (b) schematic depiction of secondary pulmonary lobule. Progress Repeat history revealed that 6 months before presentation he had moved into an old thatched cottage. Symptoms had begun a few months later. Sometimes the antigen responsible cannot b e identified, but this story raises the possibility of a fungus being responsible. Aspergil lus precipitins were negative and there- fore further fungi were tested on agar diffusion ( Ouchterlony) plates. CASE 8 59 Patient serum placed in this well Known Serpula lacrymans in this well Preparation from the patient \200\231s house roofing timbers Fig. 8.3 Ouchterlony results. Questions 8g) What does the Ouchterlony plate in Fig. 8.3 show? 8h) What is the cause? 8i) What is the treatment? CASE HISTORIES IN RESPIRATORY MEDICINE 60 Answers 8g) What does the Ouchterlony plate in Fig. 8.3 show? Precipitin lines have formed where antigen (peripheral wells) meets precipitating antibody (central well) ( Fig. 8.3 ). More detailed analysis showed there was more than one line, in dicating that the patient was making IgG to more than one epitope on Serpula lacrymans . Th e number of lines is roughly proportional to the degree of immunological reaction to the fu ngus. 8h) What is the cause? Serpula lacrymans is the main fungus causing dry rot. It is called lacrymans, not because y ou cry when you find it in your house, but because water drops often form on the fungus, li ke tears ( Fig. 8.4 ). Fig. 8.4 Serpula lacrymans on rotting wood. 8i) What is the treatment? Hypersensitivity pneumonitis (histology shown in Fig 8.5) responds well to steroids with ra pid relief of symptoms, as occurred in this case. Once the dry rot had been identified in t he roof, the patient sold his cottage as quickly as possible, thus removing himself from th e antigen. CASE 8 61 Fig. 8.5 Lung biopsy showing small, poorly-formed non-caseating granulomas, located near re spiratory or terminal bronchioles (courtesy of Dr C. Clelland). With thanks to Prof Rob Davies for permission to report this case, and to Dr Graham Bird (d eceased), who first recognized that dry rot was the explanation. Further reading Bryant DH , Rogers P ( 1991 ). Allergic alveolitis due to wood-rot fungi . Allergy Proc ; 1 2 : 89 \200\223 94 . Case 9 An 18-year-old student had bilateral pneumothoraces, which had not resolved with simple asp iration and chest drain insertion. She therefore underwent bilateral pleurectomy, during wh ich it was observed she had multiple small cysts over the surfaces of her lungs. She made a good recovery, although was left with a chronic left pneumothorax. Histology of a lung bio psy at the time of surgery is shown in Fig. 9.1 , and her CXR and CT chest in Fig. 9.2a and b . She had never smoked, and her only past medical history was of a renal angiomy- olipom a, for which she underwent a left nephrectomy aged 13. A B C Fig. 9.1 Histology of lung biopsy, taken at the time of surgery, with H&E stain. Features A to C are referred to in Answer 9a. Questions 9a) What features are illustrated in Figs 9.1 and 9.2 ? 9b) What conditions cause pulmonary cysts, and what radiological features distinguish them? 9c) What is the most likely diagnosis? CASE 9 63 (a) (b) Fig. 9.2 (a) CXR and (b) CT chest. CASE HISTORIES IN RESPIRATORY MEDICINE 64 Answers 9a) What features are illustrated in Figs. 9.1 and 9.2? Histology ( Fig. 9.1 ) shows the presence of cysts (see label A), and areas of focal smooth muscle proliferation (B). Alveoli with distorted architecture are seen to the left of the image, probably crush artifact (C). The CXR ( Fig. 9.2a ) shows a left-sided pneumothorax, with lucency at the left base, and t he lung edge visible up to the left apex. There is apparent interstitial shadowing without thoracic volume loss (e.g. see enlarged portion). Interstitial shadowing on a CXR is often due to fibrosis, and so associated with volume loss. Interstitial shadowing without volume loss is unusual, and should make one think of these three conditions: \227\206 Lymphangioleiomyomatosis (LAM) \227\206 Langerhans cell histiocytosis (LCH, or histiocytosis X) \227\206 Lymphangitiis. In both LAM and LCH the lung parenchyma is essentially normal; how- ever, the presence of m ultiple cysts gives the false impression on plain CXR of interstitial shadowing and reticul ae (lines). As there is normal parenchyma, lung volumes are not reduced, as they would be i n fibrotic conditions. In pure lymphangitiis, again the parenchyma is normal, but malignant spread through pulmonary lymphatics produces interstitial shadowing on the CXR. The HRCT chest ( Fig. 9.2b ) shows the left pneumothorax, and multiple small thin-walled cy sts scattered evenly throughout the lung fields. This widespread distribution is typical of LAM. The intervening lung paren- chyma appears normal. 9b) What conditions cause pulmonary cysts, and what radiological features distinguish them? Pulmonary cysts may arise in: \227\206 Lymphangioleiomyomatosis (LAM) \227\206 Langerhans cell histiocytosis (LCH) \227\206 End stage pulmonary fibrosis with honeycombing. Cysts are round spaces with well-defined walls, which are usually air- containing when in t he lung, though may also contain fluid. Their walls are made up of respiratory epithelium, cartilage or smooth muscle. In contrast, bullae are usually present in emphysema. These are air-filled spaces, with thin walls (<1mm) made up of pleura, septa or compressed CASE 9 65 (a) (b) Fig. 9.3 (a) CXR and (b) HRCT chest of a patient with Langerhans cell histiocytosis. This r are granulomatous condition is associated with smoking. It has a mid- and upper-zone predom inance, whereas LAM affects all zones equally. Characteristic features of the CT scan are \200\230bizarre \200\231 or irregular-shaped cysts and nodules. In LAM cysts are regular, a nd nodules are not present. CASE HISTORIES IN RESPIRATORY MEDICINE 66 (a) (b) Fig. 9.4 (a) CXR and (b) CT chest of a patient with severe COPD with bullous lung disease. On the CXR there is a focal region of low attenuation in the left mid-zone, without visible walls, due to a massively enlarged air space. On CT scan, bullae are large and irregular, with no or thin walls. The bullae often have a central vessel, distinguishing them from cys ts. CASE 9 67 (a) (b) Fig. 9.5 (a) CXR and (b) CT chest of a patient with end-stage pulmonary fibrosis secondary to usual interstitial pneumonitis (UIP). The chest XR shows markedly reduced thoracic volum es. The cysts on the CT are peripheral and thick walled. CASE HISTORIES IN RESPIRATORY MEDICINE 68 lung tissue. Distinguishing radiological features of LCH, emphysema and fibrosis are highli ghted below (Figs 9.3, 9.4 and 9.5). 9c) What is the most likely diagnosis? Lymphangioleiomyomatosis (LAM) dyspnoea, multiple pneumothoraces, the previous history of a n angiomyolipoma and characteristic CT changes are all highly suggestive of LAM. In such ca ses it is not essential to obtain a histological diagnosis. LAM is a rare condition in which abnormal smooth muscle cells progres- sively accumulate in the lungs and lymphatics. Abnormalities in the pro- teins tuberin and hamartin (which usua lly attenuate smooth muscle growth), are found within LAM tissue. It has a prevalence in sp oradic cases of 1 in 1,000,000. It is much more common in patients with the genetic disease tuberous sclerosis, where signs of LAM can be identified in up to 40% of adult females. It almost exclusively affects females, generally devel- oping between menarche and the menopa use, with a mean age of onset in the mid-30s. The first symptom in most patients is either dyspnoea or pneumothorax. Less common presentations are cough, haemoptysis or chylous pleur al effusions. Occasionally abdominal symptoms and signs precede respiratory symptoms. Physi cal examination is often normal early in the disease unless a pneumothorax or chylous effus ion is present, although a minority of patients have crackles and wheeze. Other CT features of LAM besides those illustrated above are angiomyolipomas (consisting of fat, smooth musc le and thick walled blood vessels), lymphangi- oleiomyomas (proliferation of smooth muscle cells in lymph vessels causing collections of chylous fluid) and chylous pleural or ascitic collections. Survival in LAM is around 70% at 10 years, although this is highly variable. All patients with LAM should undergo evaluation for stigmata of tuberous sclerosis since th ese conditions often co-exist, with tuberous sclerosis occur- ring in 15% of women with LAM . These include periungual fibromas, facial angiofibromas, Shagreen patches (yellowish-pink firm skin plaques with a pebble-like texture) and hypomelanotic patches. Progress report Over the next 4 years she remained stable, with a chronic left pneumothorax, and only mild exercise limitation. She was keen to fly in order to see her parents who live overseas. Her CXR showed no progressive changes. Full pulmonary function tests were carried out ( Table 9.1 ). CASE 9 69 Table 9.1 Pulmonary function tests Measured SaO2(%) 97 FEV1(L) 1.6 (53% pred) FVC(L) 2.0 (56% pred) FEV1/FVC ratio 78% FRC(L) 3.2 (120% pred) body plethysmographic method RV(L) 2.4 (190% pred) body plethysmographic method TLC(L) 4.5 (99% pred) body plethysmographic method 3.0 (67% pred) helium dilution method TLCO(mM/min/kPa) 4.99 (51% pred) KCO(mM/min/kPa/L) 1.86 (86% pred) Questions 9d) Describe the pulmonary function tests. What is the estimated size of the trapped, non-c ommunicating air (this includes the pneumothora- ces and cysts)? What other method might he lp quantify the size of a pneumothorax? 9e) What is the theoretical risk of flying, and how would she conventionally be advised? CASE HISTORIES IN RESPIRATORY MEDICINE 70 Answers 9d) Describe the pulmonary function tests. What is the estimated size of the trapped, non-c ommunicating air (this includes the pneumothora- ces and cysts)? What other method might he lp quantify the size of a pneumothorax? In this case, pulmonary function tests show a restr ictive defect, with pro- portionate reduction in FEV 1 and FVC. This is likely to be due to her pneumothorax. In many patients, airflow obstruction predominates potentially leading t o a mis-diagnosis of COPD. The two methods of measuring TLC give different values. Body plethys- mography measures tot al volume within the thorax, whereas helium dilution only measures gas in communication wit h the airways within the time of the 10-second breath hold, thus excluding gas in pneumotho races and cysts. The difference between the two gives the size of the non-communicating gas : 4.5 \200\223 3.0 = 1.5L. Estimations of pneumothorax size may also be made from a CXR or CT chest. 9e) What is the theoretical risk of flying, and how would she conventionally be advised? Oxygen saturation is normal; however, trapped gas within the thorax may put her at risk. At mospheric pressure decreases with ascent to altitude ( Fig. 9.5 ). At sea level atmospheric pressure is 101kPa (760mmHg). Commercial aircraft cruising altitude 40000 Everest 35000 30000 25000 ) t e e f ( Mount Blanc La Paz 20000 e d u t i t l Lowest permissible air cabin pressure 15000 A Average air cabin pressure 10000 Sea level 5000 0 (mmHg) 100 200 300 400 500 600 700 Atmospheric pressure 0 75 100 25 50 (kPa) Fig. 9.6 Fall in atmospheric pressure with altitude. CASE 9 71 Table 9.2 Screening for in-flight oxygen supplementation using SaO 2 Screening result Recommendation Sea level SaO 2 >95% Oxygen not required Sea level SaO 2 92 \200\22395% and no risk factor Oxygen not required Sea level SaO 2 92 \200\22395% and additional risk factor * Perform hypoxic challenge test with arterial or capillary measurements of PaO2 Sea level SaO 2 <92% In-flight oxygen Receiving supplemental oxygen at sea level Increase the flow whilst in flight Additional risk factors are hypercapnia, FEV 1<50% predicted, lung cancer, fibrosis, scolio sis or respiratory muscle weakness, ventilator support, cerebrovascular or cardiac disease, within 6 weeks of discharge for an exacerbation of chronic lung or cardiac disease. Commercial aircraft fly at about 30 \200\22340,000ft, but are required to pressu- rize the cabin to at least equivalent to 8000ft, or 73kPa (548mmHg). This is equivalent to breathing 15% oxygen at sea level. This drop in inspired oxygen tension is likely to be well-tolerat ed in this patient who is not hypoxic. In healthy people, arterial oxygen tension would be expected to fall to about 7.0 \200\2238.5kPa (53 \200\22364mmHg) with SaO 2 85 \200\22391%. Sea-level oxygen saturation is used as a screening test to determine whether sup- plementa ry oxygen is required in flight, according to British Thoracic Society recommendations ( Ta ble 9.2 ). If results are equivocal, a hypoxic challenge test breathing 15% inspired oxygen for 15 minutes may be car- ried out ( Table 9.3 ). None of these recommendations are evide nce-based. Of much greater concern than hypoxia in this case is the expansion of trapped ga s with increasing altitude. If allowed to expand freely, 1.5L of trapped gas in the pneumot horaces and cysts would increase inversely proportionately to the drop in atmospheric press ure, ie. to 1.5 \227 760/548 = 2.1L. The theoretical risk is that increased air pressure i nside the pneu- mothorax might lead to pain due to stripping of pleural adhesions, rupture and bleeding. Table 9.3 Recommendation depending upon results of hypoxic challenge test (15% O 2 at sea l evel for 15 minutes) Hypoxic challenge result Recommendation PaO2 >7.4kPa (>55mmHg) Oxygen not required PaO2 6.6 \200\2237.4kPa (50 \200\22355mmHg) Borderline. A walk test may be helpful. PaO2 <6.6kPa In-flight oxygen (2L/min) CASE HISTORIES IN RESPIRATORY MEDICINE 72 Ordinarily the presence of a closed pneumothorax is an absolute contrain- dication to air f light, and arbitrarily patients are advised to wait 7 days after resolution of pneumothorax before air travel. In this case, however, the relative risk was considered low, since the pneumothorax was chronic, with pleural thickening and significant surrounding fibrosis redu cing the risk of tissue tearing. Given the exceptional nature of this case, decompression i n a hypobaric chamber was arranged, in step intervals to 10,000ft. Very minor chest discomf ort was noted between 7500 and 8000ft, but she remained well. After discussion with the air line medical officer, she was permitted to fly, and had no adverse effects. In actual fact, cabin pressure is much more commonly pressurized to the equivalent of 3000 \200\223 4000f t rather than the minimum of 8000ft. CASE 9 73 Question 9f) Discuss issues to consider in her long-term management. CASE HISTORIES IN RESPIRATORY MEDICINE 74 Answer 9f) Discuss issues to consider in her long-term management. Patients with rare conditions such as LAM can often feel isolated, and may benefit from bei ng put in touch with the relevant patient support group, LAM action (web address: www.lamac tion.org ). Current treatments are aimed at managing complications: \227\206 In the case of a second pneumothorax or a persistent air leak, early involvement of a thoracic surgeon is advised. \227\206 Chylous collections tend to re-accumulate in a short time, if managed with simple drainage, and therefore obliteration of the pleural space or ligation of the thoracic duct is recommended. Reduction in lymphatic formation by strictly controlling dietary fat or su bstitution of fat by medium-chain triglycerides, which are absorbed from the intestine and carried in blood rather than lymphatics, is difficult for patients to adhere to and has gen erally not been very successful. \227\206 Lung transplant may be considered in severe, end-stage LAM. There are not yet treatments proven to slow disease progression. Estrogen receptors are exp ressed aberrantly in the lungs, and so, theoretically, proges- terone may slow progression, and estrogen speed progression; however, hormonal treatments such as tamoxifen or medroxyp rogesterone acetate have been found to be poorly effective, as have dietary manipulations. Pregnancy may put patients at risk due to hormonal effects, and because of the risk of resp iratory compromise. Other approaches, such as use of the antiproliferative agent Rapamycin, are undergoing further evaluation. Further reading British Thoracic Society Standards of Care Committee ( 2002 ). Managing passengers with res piratory disease planning air travel: British Thoracic Society recommendations . Thorax ; 5 7 : 289 \200\223 304 . Glassberg MK ( 2004 ). Lymphangioleiomyomatosis . Clinics in Chest Med ; 25 : 573 \200\223 582 . Johnson S ( 2006 ). Lymphangioleiomyomatosis. Series \200\230rare interstitial lung diseases \200\231 . Eur Respir ; 27 : 1056 \200\223 1065 . \200\230LAM action \200\231, patient support group and case registration web address : www .lamaction.org (accessed 1st September 2009) Case 10 A 49-year-old man was referred from the hematology clinic with 18 months of breathlessness on exertion, a non-productive cough, and wheeze. He had been diagnosed with follicular lymphoma 4 years previously, and had received extensi ve chemotherapy, as well as chest radiotherapy, a year later. One year after that, and 2 ye ars prior to this presentation, he underwent an allogeneic bone marrow transplantation (BMT , sibling donor), which had been complicated by development of chronic graft-versus-host di sease affect- ing his eyes and mouth. He had never smoked and there was no prior history of any lung disease. His current medications included prednisolone 10mg once a day, cyclosporin 50mg twice a day , penicillin V 250mg twice a day, acyclovir 200mg twice a day, fluconazole 50mg once a day, co-trimoxazole 960mg 3 times a week, alendronic acid 70mg weekly, and omeprazole 20mg once a day. Becotide 200 g 2 puffs twice a day had been started by the referring team with lit tle impact on his symptoms. On examination his oxygen saturation was 97% on room air and he had scattered wheezes and squawks on auscultation. Investigations \227\206 FBC, U&Es and LFTs were all within normal limits \227\206 CXR and pulmonary function tests are shown in Fig. 10.1 and Table 10.1 . CASE HISTORIES IN RESPIRATORY MEDICINE 76 Fig. 10.1 CXR. Table 10.1 Pulmonary function tests Measured % Predicted FEV1(L) 2.4 65 FVC(L) 4.6 100 FEV1/FVC ratio (%) 53 VA(L) 5.4 77 TLCO(mmol/min/kPa) 6.05 58 KCO(mmol/min/kPa/L) 1.47 75 CASE 10 77 Questions 10a) What does (i) the CXR and (ii) the pulmonary function testing show? 10b) What is the likely diagnosis? What differential diagnoses would you consider? 10c) How would you manage this patient? CASE HISTORIES IN RESPIRATORY MEDICINE 78 Answers 10a) What does (i) the CXR and (ii) the pulmonary function testing show? The CXR shows hype r-inflation together with para-mediastinal fibrotic change in keeping with his previous rad iotherapy exposure. Bi-apical pleural thickening and a tented right hemi-diaphragm are also present. (ii) His lung function tests show moderate airflow obstruction with reduced gas t ransfer. 10b) What is the likely diagnosis? What differential diagnoses would you consider? The likely diagnosis is chronic pulmonary graft-versus-host-disease (GVHD) with bronchiolit is obliterans (also called obliterative bronchi- olitis), mainly suggested by the obstructi ve defect and clinical context. The differential diagnosis might include adult onset asthma or other causes of bronchioliti s. These are clearly less likely than chronic GVHD with pul- monary involvement, resulting in symptomatic airflow obstruction. The occurrence of bronchiolitis obliterans (BO) is not limited to those who develop chronic GVHD; it is also seen in some BMT patients without sig - nificant GVHD, and other lung insults, such as infection and irradiation, are thought to contribute. GVHD is usually associated with a severe form of BO which is very similar to th at seen in lung transplant recipients. The following points should be borne in mind: \227\206 Minor asymptomatic decrements in lung function are common post- BMT, and a histor y of acute or chronic GVHD, older recipient age and early respiratory viral infection post- transplant are recognized risk factors. \227\206 Symptomatic airflow obstruction post-BMT is more common in adults than children a nd occurs more frequently following allogeneic BMT. The exact pathogenesis remains elusive and disease is mild in most cases. \227\206 Chronic (>100 days post-BMT) GVHD arises in up to 50% of patients who survive 6 m onths, and direct pulmonary involvement is com- mon. The risk of other non-infectious pulmo nary complications (see Table 10.2 ) is also increased by chronic GVHD, which itself is ass oci- ated with marked immunosuppression, made worse by the drugs used to treat it. Clinical ly dyspnoea, a non-productive cough and wheeze (+/ \200\223 crackles and squawks) are seen at a median post-transplant time of 5 months. The CXR may be normal, but lung function indi cates airway obstruction unresponsive to bronchodilators. Histologically, CASE 10 79 Table 10.2 Other pulmonary complications occurring late (>100 days) post-BMT Infection Risk is reduced with prophylaxis with antibiotics Idiopathic pneumonia syndrome Diagnosis of exclusion with associated high mortality Diffuse alveolar hemorrhage Underlying infection common, mortality high Secondary alveolar proteinosis Reported following transplantation for acute leukemia. BAL positive for lipoproteins Secondary malignancies Underlying malignancy may relapse. Epstein-Barr virus related lymphoma can involve the lung Radiation pneumonitis Radiation induced pulmonary fibrosis, may take 6 \200\22324 months to develop and can devel op in areas not irradiated Pulmonary veno-occlusive disease Rare. Patients dyspnoeic but lung function normal with no signs of infection. Right heart c atheterization shows pulmonary hypertension and lung biopsy confirms the diagnosis pulmonary GVHD may manifest as diffuse alveolar damage, lym- phocytic interstitial pneumoni a (LIP), lymphocytic bronchitis or bronchiolitis obliterans. \227\206 Bronchiolitis obliterans may produce severe symptomatic airflow obstruction in be tween 2% and 14% of patients post-allogeneic BMT. Histologically the small airways are dest royed; fibromyxoid granula- tion tissue causes this small airway obliteration. It is almost exclusive to recipients with chronic GVHD, which has led to the hypothesis that the small airway obliteration is a pulmonary manifestation of GVHD (with bronchiolar epithelial cells targeted by cytotoxic donor T lymphocytes). The exact pathophysiology, however, is unknown ; other factors postulated to mediate persistent small airway inflamma- tion include viral infections, inadequate immunosuppression, low serum IgG, and gastro-oesophageal reflux. 10c) How would you manage this patient? Management should include: \227\206 Augmentation of immunosuppressive therapy (guided by the refer- ring hematology team) Increase in oral prednisolone dose (this is often tried first line) Increase dose of other immunosuppressive agents CASE HISTORIES IN RESPIRATORY MEDICINE 80 Methotrexate, cyclosporin and azathioprine may be used in addi- tion to prednisolone Thalidomide, methylprednisolone, hydroxychloroquine, tacrolimus and TNF antagonists have also been studied \227\206 Optimization of bronchodilator medication Long-acting bronchodilators High-dose inhaled corticosteroids \227\206 Exclusion of concomitant infection \227\206 Prompt treatment of infection (to avoid decline in airflow obstruction and bronchiectatic exacerbations) \227\206 High-resolution CT scan to confirm likely diagnosis and exclude alternatives \227\206 Surveillance with monitoring of lung function/symptoms \200\224the sever- ity and progression of chronic GVHD related airflow obstruction is best assessed by regular monito ring of FEV 1 . There are no prospective studies to guide the definitive treatment of post-BMT airway obstr uction. Most treatment approaches address underlying chronic GVHD with corticosteroids the mainstay of treat- ment for BO. Unfortunately BO is often poorly responsive to therapy. Progress Combination therapy (long-acting bronchodilators and inhaled corticosteroid) was commenced but, despite this, the FEV 1 fell from 2.4 to 1.9. A thoracic CT was performed ( Fig. 10.2 ). Questions 10d) What does the CT show? 10e) What would you do next? 10f ) What other treatment strategies could be considered? CASE 10 81 (a) (b) Fig. 10.2 Two slices from CT chest. CASE HISTORIES IN RESPIRATORY MEDICINE 82 Answers 10d) What does the CT show? His CT reveals para-mediastinal radiotherapy change with mild bron- chiectasis. A mosaic pa ttern of attenuation, consistent with areas of air-trapping, and subtle paucity of peripher al vascularity is seen. 10e) What would you do next?