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. On histology, organizing pneumonia with obliterative bronchiolitis may be seen in the conte xt of several interstitial diseases \200\224the absence of histological evidence of other d isease within the same biopsy specimen suggests the diagnosis of COP. 33g) How would you investigate this patient further? Investigations are guided by the above differential diagnosis. Establishing a diagnosis rel ies on a combination of clinical and radiological features, and may require histopathologic al confirmation. To narrow the differential diagnosis: \227\206 A thorough history (including possible HP antigens, new medication and symptoms of a CTD) should be taken \227\206 Blood eosinophil count should be measured \227\206 Auto-antibodies may be reasonable, if there is a question of an associ- ated CTD (e.g. anti-Jo1 especially in the context of myalgia) \227\206 Bronchoalveolar lavage is a useful investigation to exclude other causes, specifi cally infection or malignancy (in the presence of an atypical radiological pattern, e.g. BA C); BAL findings are not specific to COP (e.g. increased cellularity, foamy macrophages, et c.) and therefore are not useful solely for diagnosis \227\206 Transbronchial biopsies \200\224please see below. CASE 33 281 Progress The patient proceeded to transbronchial biopsy (TBB), which showed clear evidence of organi zing pneumonia and obliterative bronchiolitis, and no evi- dence of infection or granuloma formation. Questions 33h) Discuss the pros and cons of further attempts at tissue diagnosis. 33i) Describe treatment options and prognosis. CASE HISTORIES IN RESPIRATORY MEDICINE 282 Answers 33h) Discuss the pros and cons of further attempts at tissue diagnosis. Lung histology \200\224 there is some debate as to whether lung histology (i.e. at open or VATS lung biopsy) is always required for diagnosis. Obtaining lung histology (on larger se ctions of lung than is provided by TBB) is aimed at confidently excluding other pathologica l processes (e.g. NSIP, eosi- nophilic pneumonia, vasculitis). This is relevant to COP, as the patho- logical lesion (described in 33f) may be present in a number of non-COP lung dis eases, and TBBs alone may not exclude these entities. However, the risks of lung biopsy should be considered, as many of these patients are hypox ic at presentation, although this is not usually severe. Given that COP is generally very t reatment responsive (see below), in the presence of supportive TBB results, a course of tre atment may be used as a therapeutic and diagnostic strategy. Some authorities in the UK wou ld therefore treat a typical case having excluded other diagnoses (e.g. by TBB) on the basi s of typical clinical and radiographic appearances rather than insisting on lung biopsy. A diagnosis of COP often commits patients to months of steroid therapy, with all the associ ated risks and potential complications. Depending on the case in question, it may be reason able to treat initially without histo- logical confirmation and proceed to biopsy in the ca se of unresponsive or relapsed disease. 33i) Describe treatment options and prognosis. COP rarely recedes untreated and generally responds well to corticosteroids, although there are no robust studies assessing treatment in this area. A reasonable regimen is as follows : \227\206 0.5 to 1.5mg/kg prednisolone once per day for 4 to 8 weeks \227\206 Gradual decrease in dose, if stable over the next 4 to 6 weeks, as tolerated to 0.5 mg/kg \227\206 If remains stable, gradual reduction of dose to 0 over 3 to 6 months. Optimal duration of therapy is not known, but is usually required for at least 3 and up to 12 months. During this period, the patient should be reviewed regularly to assess for radio logical or clinical relapse requiring an increase in steroid therapy. Other immunosuppressa nts have been advocated in those unresponsive or intolerant of steroid therapy, but no evid ence exists to inform clinical decision-making. CASE 33 283 Rapid and full recovery occurs in the majority of patients on steroid therapy within a few weeks. If relapse off treatment does occur, this does not appear to be associated with long -term reduction in lung function or functional deficit. Overall, around one-third of patien ts will experience persistent disease that may require prolonged treatment. Relapse will co mmonly occur on withdrawal of steroid therapy, and these patients should continue to be mon itored as out-patients, once symptoms and radiology have improved for several months. In rapidly progressive, aggressive disease (fulminant COP), high-dose intravenous steroid has been recommended. Further reading ATS/ERS Statement (2002): International Multidisciplinary Consensus Classification of Idiop athic Interstitial Pneumonias : http://www.thoracic.org/sections/publications/ statements/p ages/respiratory-disease-adults/idio02.html (accessed 3rd September 2009) BTS guidelines on interstitial lung disease (2008) : http://www.brit-thoracic.org.uk/ clinicalinformation/interstitiallungdiseasesDPLD/interstitiallungdiseaseDPLDguideline/ tabi d/126/default.aspx (accessed 3rd September 2009) Cordier JF ( 2006 ). Cryptogenic organizing Pneumonia . Eur Respir J ; 28 : 422 \200\223 4 46 . Case 34 A 36-year-old man with cystic fibrosis (CF) had small volume haemoptysis of 5 \200\22310ml every 3 \200\2234 days for 4 months. He was able to cycle short distances daily, although d esaturated from SaO 2 92% at rest to 70% on walking. His other medical history was of gall stones, pancreatic insufficiency (on Creon) and CF related diabetes (on insulin). He had 3 \200\2234 infective exacerbations per year requiring intra-venous antibiotics. He underwent a rapid deterioration and was admitted acutely via the emergency department wi th massive haemoptysis, coughing up 600ml blood over the course of 2h. He became haemodynam ically unstable, with a heart rate of 150bpm and BP 70/45, and was drowsy. He had had incre ased sputum purulence for the preceding few days. Investigations Blood tests: \227\206 Hb, 12.1g/dL \227\206 CRP, 157mg/L \227\206 MCV, 82fL \227\206 Urea, 6.8mmol/L \227\206 Platelets, 534 \227 10 9 /L \227\206 Creatinine, 76 m/L \227\206 WCC, 21.5 \227 10 9 /L (neutrophilia) \227\206 Electrolytes, normal \227\206 Clotting screen, normal. Spirometry at previous out-patient visit: \227\206 FEV 1 1.0L (22% predicted: steady decline from 1.75L 8 years ago) \227\206 FVC 2 .5L. Recent sputum cultures: \227\206 Moderate Staphylococcus aureus , sensitive to flucloxacillin \227\206 Moderate Pseudomonas aeruginosa sensitive to ceftazadime, gentamy- cin and colistin. See also Table 34.1 and Fig. 34.1 . CASE 34 285 Table 34.1 Arterial blood gasses During current illness: Previous sample when well: 0.40 0.21 FiO2 pH 7.02 7.39 16.6kPa 7.9kPa PaO2 20.8kPa 8.0kPa PaCO2 96% 92% SaO2 Base excess 2.4mM/L 8.6mM/L Bicarbonate 27mM/L 33mM/L Lactate 1.5mM/L Fig. 34.1 CXR. Questions 34a) Interpret the investigations outlined above. 34b) What risk factors for massive haemoptysis does this man have? 34c) What is the commonest mechanism of haemoptysis in patients with cystic fibrosis? 34d) Describe crucial steps in his immediate management in the emer- gency department (spec ialist procedures will be discussed later). CASE HISTORIES IN RESPIRATORY MEDICINE 286 Answers 34a) Interpret the investigations outlined above. Interpretation of investigations: \227\206 Arterial blood gasses show a profound respiratory acidosis, and partial loss of h is previously observed compensating metabolic alkalosis. The loss of metabolic compensation with a bicarbonate near normal, when previously high, is likely to be due to hypoxia, hypo volaemia and hypotension, causing lactate and other metabolic acid production. \227\206 Blood tests show hemoglobin is only marginally reduced and MCV is normal, in keep ing with the acute history of this bleed. Inflammatory markers are all raised (CRP, white c ell count and platelets) in keeping with active infection or an acute phase response. \227\206 Spirometry reflects severe obstructive airways disease, with a progres- sive decline over time. \227\206 Recent sputum cultures are positive for Staphyloccus aureus and Pseudomonas aerug inosa . These commonly represent long-standing colonization in CF; however, the increased s putum purulence may be due to current infection. Acute-phase reactants are non-specific, as they may be elevated in the presence of a large bleed. Recent micro- biological cultures a re often helpful in guiding preliminary treatment before current cultures are available. \227\206 The CXR shows extensive bronchiectatic changes throughout both lungs. There is a large cystic area in the left apex ( Fig. 34.2 ), which on Fig. 34.2 Portion of CXR, with arrows indicating the medial and inferior walls of the large cystic area in the left apex. CASE 34 287 comparison with previous films was not new. This particular CXR is not helpful in identifyi ng the site of bleeding. 34b) What risk factors for massive haemoptysis does this man have? Small-volume haemoptysis is extremely common in CF. The incidence of massive haemoptysis, a s in this case, is less common at around 1 in 100 patients per year, and is defined as an a cute bleed >240ml per 24h, or recurrent bleeding greater than 100ml/day over several days. Specific risk factors that this man has are: \227\206 Older age, relative to the CF population. Median age for massive haemoptysis is 2 3 years, with only patients being <18 years old. \227\206 More advanced disease: 61% of patients have an FEV 1 <40% pre- dicted, although it can occur in patients with normal lun g function. \227\206 Declining lung function. \227\206 Staphyloccoccus aureus and possibly Pseudomonas infection. 34c) What is the commonest mechanism of haemoptysis in patients with cystic fibrosis? The commonest mechanism of massive haemoptysis is rupture of a bronchial artery with passag e of blood into an airway. The underlying pathogenesis is thought to be due to persistent a irway infection and inflammation. The chronic inflammation leads to proliferation of the br onchial vasculature through bronchial artery hypertrophy and angio- genesis. It has been hy pothesized that virulence factors of S. aureus can lead to alterations in the pulmonary epi thelium and vascular endothe- lium to stimulate bronchial artery proliferation. This result s in a system of enlarged, dilated and tortuous vessels with collaterals and bronchopul- mo nary anastomoses. Haemoptysis originates from the bronchial circulation in 90% of cases, and has the propensi ty to cause massive haemoptysis as bronchial arter- ies usually arise directly from the aor ta, and therefore carry blood at systemic pressure. The bronchial circulation supplies cond ucting airways down to the terminal bronchioles, and most of this blood is carried away fro m the lung via the pulmonary veins. The flow through the bronchial circulation is a mere fr action of that through the pulmonary circulation, and the lung can function fairly well wit hout it, example.g. following lung transplantation. Bleeding from the pulmonary circulation or alveoli is much less common. CASE HISTORIES IN RESPIRATORY MEDICINE 288 34d) Describe crucial steps in his immediate management in the emergency department (specialist procedures will be discussed later). This man is critically unwell. His airway is at risk due to haemoptysis and drowsiness, put ting him as risk of aspiration. He is hypoventilating with hypercapnic respiratory failure, and he has cardiovascular instability with hypotension due to blood loss. He requires urge nt resuscitation, including: \227\206 Intubation to protect his airway, to enable mechanical ventilation and to enable bronchoscopy, if required. \227\206 Suctioning of secretions and blood may be helpful, although vigorous chest physio therapy should be avoided until haemoptysis has settled. He will require admission to an in tensive care unit. \227\206 Volume replacement with vigilant fluid balance assessment is required. \227\206 Intra-venous antibiotics as pulmonary infection contributes to on-going haemoptys is. In his case they should initially cover Staphyloccus and Pseudomonas , even though it i s not entirely clear whether these repre- sent infection or colonization. Repeat sputum cul tures should be sent to enable the antibiotic spectrum to be narrowed in due course. Note t hat, although sputum cultures are not helpful in most respiratory disease, they form an ess ential part of management of patients with cystic fibrosis or bronchiectasis, enabling appr opriate antibiotic choice. \227\206 Position with bleeding side down to prevent aspiration into the unaf- fected lung, if the side of the bleed is known. \227\206 Nebulized epinephrine (3 \200\2235ml 1:1000) may be of benefit, although is unproven for large bleeds. \227\206 Tranexamic acid can be considered; it is an anti-fibrinolytic agent and synthetic derivative of the amino acid lysine that during clot forma- tion binds reversibly to plasm inogen, blocking its binding to fibrin and subsequent activation to plasmin. This results i n the stabilization of clots by inhibition of tissue fibrinolysis. It may be given orally f or recurrent small volume haemoptysis, although its role is massive hae- moptysis is uncert ain. \227\206 Intra-venous vasopressin or subcutaneous/intra-venous octreotide have also been u sed, although caution is advised in patients with coex- istent coronary artery disease or h ypertension. CASE 34 289 Questions 34e) What vitamin deficiency should be sought in massive haemoptysis in cystic fibrosis? 34f) What further investigation and interventional procedures should be considered? CASE HISTORIES IN RESPIRATORY MEDICINE 290 Answers 34e) What vitamin deficiency should be sought in massive haemoptysis in cystic fibrosis? Patients with cystic fibrosis may have a vitamin-K deficiency related to fat malabsorption and antibiotic usage, so studies should include coagu- lation profiles. 34f) What further investigation and interventional procedures should be considered? A pulmonary angiogram and bronchial arterial embolization is recom- mended after an episode of massive haemoptysis, even if it settles. The bleeding bronchial artery is identified th rough extravasation of dye if bleeding is ongoing, visualization of tortuous vessels of inc reased caliber or aneurysmal dilatation. In this man \200\231s case, angiography showed hyp er- vascularity and an aberrant systemic arterial supply to the lungs. A large anomalous br onchial artery arising from the left thyrocervical trunk descended through the mediastinum to feed a markedly hypertrophied left bronchial artery. This bronchial artery was embolized with polyvinyl alcohol. Alternative agents are foam granules (500 \200\223700 m in diamet er) or platinum coils. Sometimes it is hard to identify the culprit vessel, and many advoca te that all large and suspicious bronchial arteries should be embolized. Bronchial artery e mbolization has been found to be safe and effective in controlling the immediate bleeding ( 96% within 24h); how- ever, the recurrence rates are greater than 50% within 4 months. Tech nical failure may arise due to non-bronchial artery collaterals from other sys- temic vesse ls. Bronchoscopy should be considered for localization of the bleeding site, and to allow thera peutic intervention. Installation of 1:20,000 epine- phrine may help control bleeding, alth ough its role in massive haemopty- sis is uncertain. Isolation of a bleeding segment with a balloon catheter allows lobar or segmental tamponade and may prevent aspiration of blood i nto the large airways. A 4-7 French 200cm balloon catheter is passed through the working ch annel of the bronchoscope, and may be left in situ for up to 24h. Leaving it in too long ma y lead to post-obstructive pneumonia or ischaemic mucosal injury. This is just a temporary measure until more definitive measures, such as embolization, can be used. If bleeding can be localized to the right or left lung, unilateral lung intubation and sele ctive ventilation may help protect the non-bleeding lung. For right-sided bleeding, a bronc hoscope may be directed into the CASE 34 291 left main bronchus, which can then be selectively intubated using the bronchoscope as a \200\230guide wire \200\231 with the patient lying in the right-lateral position. The left lung is then protected from aspiration and selectively ventilated. For a left-sided bleedin g source, the patient is placed in the left-lateral position and selective intubation of th e right lung may be performed, but this may lead to occlusion of the right-upper lobe bron- chus. Alternatively, the endotracheal tube may be passed into the tra- chea, and a Fogarty catheter (size 14 French/100cm length) may then be passed through the vocal cords beside t he endotracheal tube, directed by the bronchoscope into the left main bronchus and inflated . This pre- vents aspiration of blood from the left lung and the endotracheal tube position ed into the trachea allows ventilation of the unaffected right lung. An alternative strateg y for unilateral bleeding is to pass a double lumen endotracheal tube, which allows isolati on and ventilation of the normal lung and prevents aspiration from the side involved by ble eding. This should only be performed by experienced operators to avoid the serious conseque nces of poor positioning. Surgical resection may be carried out as a last resort for intractable bleeding from a loca lized site; however, the patient must be fit enough to withstand both the acute procedure, and the loss of lung function after- wards. It has a high mortality rate, approaching 50% i n severely ill patients. Outlook A small, retrospective study compared patients who had had massive haemop- tysis treated wi th embolization, with CF patients matched for age and FEV 1 who had not had haemoptysis or embolization. Over a period of up to 14 years, those with haemoptysis and embolization had a greater incidence of death (8/30 compared to 3/27) and lung transplant (9/30 compared wit h 1/27). They also had a numerically greater, though non-significant, increased incidence o f infection with multi-drug resistant Pseudomonas and greater decline in FEV 1 . 8/30 had r ecurrent major haemoptysis. The relative influence of infection, haemoptysis and the emboli zation process itself on lung function and outcome is not known. The gentleman in this case made a remarkably good recovery from this par- ticular episode. Unfortunately he went on to have recurrent massive haemoptysis and repeated embolizations, with step-wise deteriorations in lung function. He was referred and accepted for a lung tra nsplant, but died of a further massive haemoptysis before this was possible. CASE HISTORIES IN RESPIRATORY MEDICINE 292 Further reading Graff GR ( 2000 ). Treatment of recurrent severe hemopytsis in cystic fibrosis with tranexamic acid . Respiration ; 68 : 91 \200\223 94 . Lordan JL , Gascoigne A , Corris PA ( 2003 ). The pulmonary physician in critical care. Illustrative case 7: assessment and management of massive haemoptysis . Thorax ; 58 : 814 \200\223 819 . Stenbit A , Flume PA ( 2008 ). Pulmonary complications in adult patients with cystic fibros is . Am J Med Sci ; 335 ( 1 ): 55 \200\223 59 . Vidal V , Therasse E , Berthiaume Y, Bommart S, Giroux MF, Oliva VL et al . ( 2006 ). Bronchial artery embolization in adults with cystic fibrosis: impact on the clinical course and survival . J Vasc Interv Radiol ; 17 : 953 \200\223 958 . Case 35 A 37-year-old lady was referred to the chest clinic with a 6-week history of progressive sh ortness of breath, productive cough and malaise. She reported a several year history of pro ductive cough, recurrent chest infections and repeated courses of antibiotics. She was know n to have common variable immunodefi- ciency (CVID), which was diagnosed at the age of 19. She had undergone a splenectomy (for haemolytic anemia) and received daily treatment with p ro- phylactic penicillin and regular courses of intravenous immunoglobulin. On examination, she was clubbed, tachypnoeic at rest (25/min) with oxygen saturations of 95 % on room air. Chest examination revealed bibasal coarse crackles and a cough productive of whitish sputum. The CXR is shown in Fig. 35.1 and the pulmonary function in Table 35.1. Lung function see Table 35.1 Table 35.1 Pulmonary function tests Measured % Predicted FEV1(L) 2.3 80 FVC(L) 2.6 78 FEV1/FVC % 87 RV(L) 1.5 99 TLC(L) 4.2 85 TLCO(mM/min/kPa) 6.14 71 KCO(mM/min/kPa/L) 1.70 94 CASE HISTORIES IN RESPIRATORY MEDICINE 294 Fig. 35.1 CXR. CASE 35 295 Questions 35a) Interpret the CXR ( Fig. 35.1 ). 35b) Interpret the lung function ( Table 35.1 ). 35c) What is the differential diagnosis in this case? 35d) What further investigations would be helpful? CASE HISTORIES IN RESPIRATORY MEDICINE 296 Answers 35a) Interpret the CXR ( Fig. 35.1 ). The CXR shows bilateral mid- and lower-zone bronchial wall thickening with areas of reticul ation peripherally. In addition, there are areas of nodular consolidation in the apices. 35b) Interpret the lung function ( Table 35.1 ). There is a restrictive defect (high FEV 1 /FVC ratio, low FVC, low TLC) that is associated with a decreased gas transfer co-efficient. This is mainly due to the decrease in lung volu me as KCO is only minimally reduced. 35c) What is the differential diagnosis in this case? The history of chronic sputum production, clubbing and radiological bronchial dilatation ar e suggestive of bronchiectasis (perhaps with inter- current infection given the infiltrates ). However, lung function suggests a restrictive process (rather than obstruction, which wo uld be more typical of bronchiectasis), and some of the CXR changes (nodular con- solidatio n, peripheral fibrosis) are atypical for bronchiectasis alone and are suggestive of an addi tional process. CVID is a disease associated with hypogammaglobulinaemia, recurrent bacterial infections an d a number of immunological abnormalities. In the context of CVID, several associated lung pathologies are reported: \227\206 Recurrent rhinosinusitis \227\206 Recurrent lower respiratory tract infections \227\206 Bronchiectasis \227\206 Lymphoid tissue proliferation in the lung \227\206 Malignancy (particularly primary lung lymphoma) \227\206 Lymphocytic interstitial pneumonia. 35d) What further investigations would be helpful? A high-resolution CT is probably the most useful next investigation, to assess for bronchie ctasis and the presence of interstitial lung disease and consolidation. Sputum cultures are likely to be required given the pres- entation and underlying disease (possibility of atyp ical bacterial infec- tion, including mycobacteria). Bronchoscopy and broncho-alveolar lava ge are useful to exclude intercurrent infection, and may identify a predominant cell type ( e.g. lymphocytes), which may suggest a specific diagnosis. CASE 35 297 Progress Blood tests revealed mildly raised inflammatory markers (CRP = 47mg/L, ESR = 41mm/h) and a raised white cell count (12.4 \227 10 9 /L, 70% neutrophils). Sputum cultures showed a pro fuse growth of Pseudomonas aeruginosa (PsA). Fig. 35.2 High-resolution CT. Questions 35e) Describe the CT findings. 35f) What diagnosis or diagnoses do they support? 35g) How would you investigate and manage this patient? CASE HISTORIES IN RESPIRATORY MEDICINE 298 Answers 35e) Describe the CT findings. The CT (Fig. 35.2 and 35.3) demonstrates some bronchiectasis in associa- tion with chronic fibrotic disease, and multiple areas of peripheral con- solidation. In addition there are a reas of ground glass attenuation (see Fig. 35.3 ). Fibrosis Consolidation Bronchiectasis Fig. 35.3 Expanded portion of HRCT from Fig. 35.2. 35f) What diagnosis or diagnoses do they support? The diagnoses supported by this HRCT scan are of bronchiectasis in addition to a cause of m ulti-focal consolidation. The differential diagnosis in this context must include typical a nd atypical infections (including mycobacterial and fungal disease), lymphoid interstitial pneumonia, pulmonary lymphoma and drug reactions. 35g) How would you investigate and manage this patient? Bronchiectasis. The bronchiectasis is likely to have been caused by recur- rent infections in the past due to CVID (inadequate host defense in the bronchial tree). The patient \200 \231s clinical condition has deteriorated in the context of a positive sputum culture (PsA) and in this context, this should probably be treated with a view to microbiological eradic ation (4 \200\2236 weeks of oral ciprofloxacin with inhaled antibiotic). Some authori- ties would argue for an even more aggressive treatment strategy, as this is the first isolate o f PsA and the patient was unwell (i.e. single or dual intravenous treatment to achieve erad ication). CASE 35 299 Chronic infection with Pseudomonas is seen in up to one-third of patients with bronchiectas is, and has been associated with poorer lung function, decreased quality of life and more f requent hospital admissions. The cor- rect treatment paradigm in non-CF bronchiectasis is d ebated, with ran- domized evidence demonstrating good bacterial clearance using a combinati on of oral ciprofloxacin plus inhaled tobramycin for 14 days. However, this improvement in microbiology was not found to be associ- ated with clinical improvement, and in fact a wors ening of lung function was observed in these patients (presumably a reflection of airway re sponse to inhaled therapy). Extrapolating data from the CF population, most clinicians woul d attempt eradication of Pseudomonas in non-CF bron- chiectasis after the first isolate, al though direct evidence is lacking. BTS guidelines on this subject are due to be published i n 2009. Further well-established treatments for bronchiectasis include chest physiotherapy, patient education, microbiology directed antibiotics for exacerbations and vaccination (see case 1 ). In this case, vaccination is not useful as the patient has hypogammaglobulinaemia. Norma l investi- gation of additional causes of bronchiectasis may be equally limited in this cas e (e.g. Aspergillus precipitins). Other investigations Further investigation is required to clarify the abnormalities seen on the HRCT scan (nodul arity, infiltrates), especially if they do not clear after treat- ment for the infection. B ronchoalveolar lavage is an important investigation to exclude atypical infection (e.g. fun gi, non-tuberculous mycobacteria) and malignancy. Progress The patient underwent eradication therapy for Pseudomonas (oral cipro- floxacin and nebuliz ed colomycin for 4 weeks) with subsequent negative spu- tum cultures. The CXR abnormalities persisted, and she continued to complain of shortness of breath and malaise. Bronchoalveol ar lavage was conducted, showing no evidence of infection or malignancy, with increased num bers of lymphocytes and negative for microbiology including AFBs. A repeat CT scan 2 months later (not shown) showed increase in the infiltrate and nodularity. Question 35h) What is the differential diagnosis for these persistent CT changes and how would you proceed? CASE HISTORIES IN RESPIRATORY MEDICINE 300 Answer 35h) What is the differential diagnosis for these persistent CT changes and how would you proceed? The differential diagnosis radiologically includes lymphoid interstitial pneumonia (LIP), p rimary lymphoma of the lung and non-tuberculous mycobacteria. The negative lavage makes non -tuberculous mycobacteria highly unlikely. LIP is not bronchocentric in nature, and therefore transbronchial biopsies are unlikely to be helpful, and produce too small a sample to assess for lymphoma (transbronchial biopsies may be useful in this context as an aid to the diagnosis of atypical infection, but will no t help to achieve one of the diagnoses above). An open lung biopsy is, therefore, reasonabl e, to enable firm diagnosis, treatment and prognostication. CASE 35 301 Progress She underwent open lung biopsy, histology of which showed an interstitial infiltrate of lym phocytes and plasma cells along the alveolar septae, with no evidence of clonality. Questions 35i) What is the diagnosis? 35j) How would you manage this condition? 35k) What diseases is it associated with? CASE HISTORIES IN RESPIRATORY MEDICINE 302 Answers 35i) What is the diagnosis? The histology is consistent with a diagnosis of lymphoid interstitial. pneumonia (LIP). The disease is defined as a dense interstitial lymphoid infiltrate (including lymphocytes, pla sma cells, histiocytes) with exten- sive infiltration of the alveolar septae. There are lym phoid follicles and lymphoid hyperplasia present within the pulmonary lymphatics and non-ca seating granulomas may be seen. Lymphoid interstitial pneumonia is an uncommon disease classified within the idiopathic int erstitial pneumonias. It most commonly affects female patients in the fifth decade, and usu ally presents insidiously with increasing cough and breathlessness over a period of years. LIP is usually associated with another disease (see answer 35k). \227\206 Radiological features. LIP may present in a wide variety of radiological patterns . Two main CXR patterns have been described: basal intersti- tial changes associated with a ir space shadowing, and diffuse airspace involvement associated with honeycombing. On CT, g round glass shadowing is usually seen and may be associated with peri-vascular honeycombing or cyst formation. Multi-focal nodularity +/ \200\223 consoli- dation and reticulation may also be seen. \227\206 Diagnosis is made on the basis of clinical suspicion (especially in the presence of associated disease states as below) plus histology. The radiological features of LIP may occur in many infective/inflamma- tory diseases, and therefore histological proof is usual ly sought. The main differential diagnosis (once infection has been excluded) is of pulmona ry lymphoma, in which case a clonal population of lym- phocytes is seen, and there may be e vidence of tumor tracking along the lymphatics. Whereas LIP was previously considered to be a pre-malignant condi- tion that inevitably dev eloped in to lymphoma, only a small number of cases have been shown to follow this pattern and the majority of cases should be considered to be non-malignant. 35j) How would you manage this condition? Oral corticosteroids are the usual form of treatment, with radiological monitoring of respo nse, although there are no trials on which to base practice in this rare disease. Authoriti es recommend a prednisolone dose of 0.75 \200\2231mg/kg bodyweight for 8 to 12 weeks initia lly, followed by CASE 35 303 an attempt to reduce dose. Cases may resolve spontaneously, although around one-third progr ess to diffuse lung fibrosis. In this case, steroid treatment resulted in a dramatic clinic al and radiological improvement. Over the following 2-year period, high doses of steroids w ere required, however, and were associated with significant complications. Prognosis and required length of therapy is unknown. In around one- third of patients, prog ression occurs associated with poor prognosis, resulting in death in a median of 20 months. 35k) What diseases is it associated with? Associated conditions: \227\206 Auto-immune conditions, e.g. rheumatoid arthritis, SLE, haemolytic anemia, myasthenia, pernicious anemia, thyroid disease \227\206 Sj gren \200\231s syndrome (one-fourth of cases of LIP are reported to be