Case 15 A 51-year-old man was referred with bouts of coughing followed by syncope. He described one initial episode of syncope following a sudden bout of cough- ing 18 months previously, and had been free of symptoms until 3 months ago. He described a persistent cough most days, n ot worse at any particular time of day or night (not wakening him at night) and not associa ted with any other respiratory, nasal or reflux symptoms. He had two or three episodes each week, where he rapidly lost consciousness following a few short coughs; this included one episode when he was driving his Heavy Goods Vehicle (as a refuse collector for the local co uncil). He had never smoked, and had been tak- ing citalopram for mild depression, and lisi nopril for hypertension for the last 3 years. Full cardiovascular, respiratory and neurolog ical examinations were normal. CXR and spirometry were also normal. Questions 15a) How would you further investigate and manage this patient? 15b) What is the pathophysiology of cough syncope? 15c) What advice would you give to this patient about driving? CASE HISTORIES IN RESPIRATORY MEDICINE 120 Answers 15a) How would you further investigate and manage this patient? The 2 key issues are managing the cough and the complicating factor, cough syncope. The most important first step in managing this patient is the cessation of his ACE inhibito r. ACE inhibitors cause cough through excess bradyki- nin production, which sensitizes the cough reflex. Cough can develop even years after starting treatment. Following cessation of ACE inhibi- tors, median time to cough resolution is about 4 weeks but often takes longer (up to 10 months has been reported). Continued use of ACE inhibitors makes management of co ugh related to an additional pathol- ogy particularly difficult. The patient must be switch ed to an alternative antihypertensive. Angiotensin II receptor antagonists do not provoke c ough. If the cough persists after an acceptable time off an ACE inhibitor (e.g. 3 months) then a management strategy for chronic cough is required. The three most common causes of chronic cough (defined as cough >8 weeks duration), in the absence of any specific clues from either history, examination or baseline investigations ( as in this case), are: \227\206 asthma syndromes (cough variant asthma, eosinophilic bronchitis) \227\206 reflux disease (gastro-oesophageal reflux, laryngo-pharyngeal reflux, oesophageal dysmotility) and \227\206 sinonasal disease, e.g. allergic or non-allergic rhinitis, sinusitis (often terme d post-nasal drip, PND) or upper airway cough syndromes (UACS). The best way of establishing a precise diagnosis is usually with sequential trials of treat ment, in combination with selected diagnostic testing. Peak flow monitoring to look for diu rnal variability is worthwhile, but is usually normal in \200\230cough-variant \200\231 as thma. Histamine or methacholine challenge testing has high sensitivity for asthma, so may b e helpful as a \200\230rule-out \200\231 test, but lacks specificity and will not rule out eosinophilic bronchitis. Ambulatory pH monitoring will not identify \200\230non-acid \200 \231 reflux, but is helpful in the small proportion of patients who may ulti- mately be con sidered for surgical management of reflux (e.g. Nissen \200\231s fundoplication) where some form of pre-operative objective diagnostic information is advisable. In a unit receiving referrals primarily from general practice, asthma would be the most com mon diagnosis, followed by reflux, then PND/UACS. CASE 15 121 It is always possible that patients may have more than one contributing factor to their cou gh. Each therapeutic trial should last at least 3 months; some centers would argue for 6 mo nths for reflux, with additional use of pro-kinetic agents, e.g. metoclopramide (10mg three times a day). A suggested therapeutic strategy is given in Fig. 15.1 . Experience from spe - cialist clinics suggests this approach can achieve improved symptoms in over 80% of patie nts. At each point in the process it is important to emphasize the importance of compliance and the need for patience (on both physician and patients \200\231 part!). Particular care is needed in ensuring patients are instructed on how to use any inhaler device and appropr iate administration of topical nasal medication. If such an approach is not successful, further investigation (e.g. HRCT, bronchoscopy) is w arranted to look for the more unusual causes of cough (such as bronchiectasis or tracheal a myloid). In specialist clinics, Give inhaled corticosteroid (800mcg BD beclomethasone or equivalent), 3 months Cough no better. Stop asthma treatment, trial of reflux treatment Cough resolved. Diagnosis is asthma / eosinophilic bronchitis. Continue asthma treatment Cough better, but still persistent symptoms. Continue asthma treatment and consider additio nal reflux treatment Twice daily PPI (e.g. lansoprazole 30mg BD) \200 15mls gaviscon QDS (after meals and befo re bedtime) \200 Refllux avoidance measures (e.g. avoid caffeine, alcohol, elevate head o f bed) Cough better, but still persistent symptoms. Continue reflux ( asthma) treatment and cons ider additional PND/UACS treatment Cough resolved. Diagnosis is reflux ( asthma), continue reflux ( asthma) treatment. Cough no better. Stop reflux treatment, trial of PND/UACS treatment 3 weeks of nasal decongestants followed by topical nasal steroid (e.g. fluticasone 100mcg e ach nostril BD) Fig. 15.1 Suggested algorithm for treatment trials for chronic unexplained cough in presenc e of normal CXR and spirometry. CASE HISTORIES IN RESPIRATORY MEDICINE 122 up to 20% of patients may not have a cause for their cough identified (so called idiopathic chronic cough). Treatment of cough syncope involves treatment of the underlying cause of the cough. There a re no additional specific treatments for cough syncope, although atropine has been found to be effective in a single, blind, randomized controlled trial of patients with vasovagal sy ncope (Santini et al . 1999). From the cough syncope point of view, investigations would include resting 12 lead ECG and referral for more prolonged ECG monitoring, given his occupation and Driver and Vehicle Lic ensing Authority (DVLA) regulations. A variety of cardiac electrophysiological abnor- malit ies have been reported as causing cough syncope (sinus arrest, Mobitz II atrioventricular b lock, complete heart block) and permanent pacemaker insertion may be necessary if a signifi cant bradyarrythmia is demonstrated. 15b) What is the pathophysiology of cough syncope? The mechanism of cough syncope has been debated since its first descrip- tion in 1876 by Ch arcot. There is no doubt that reduced intra-cerebral blood flow is the final common pathway for its occurrence, but how this results is not entirely clear, particularly if one is not able to demonstrate a bradyarythmia on continuous ECG monitoring that includes an event. An early view proposed that, with prolonged coughing, the increased intrathoracic pressure reduced venous return to the heart and conse- quently a fall in the cardiac output, as occu rs in a Valsalva maneuver. This was demonstrated in 27 patients with continuous coughing (S harpey-Shafer 1953) but would not explain why syncope can occur after just a few coughs. A later view suggested that increased cerebral venous pressure, rather than reduced perfusion pressure, was to blame, whereby the increased intrathoracic pressure is transmitted to the cere- bral circulation via the great veins with resultant decreased cerebral blood flow de spite preserved arterial pressure (Mattle et al . 1995). This theory is contradicted by mor e recent work, which again comes down on the side of a neurally mediated reflex causing sys temic hypotension, similar to an ordinary vaso-vagal event (Benditt et al . 2005). In this study, 9 patients with cough syncope were compared with two other groups: 13 syncope patien ts exhibiting a positive tilt test, and 18 patients with unexplained syncope. The cough syn cope patients demonstrated a much greater fall in systolic blood pressure (median of 50mmHg ) com- pared to the other two groups in response to two \200\230vigorous, volatile \200 \231 CASE 15 123 coughs. This was accompanied by a blunted heart-rate response to the hypotension, and a slo wer recovery of blood pressure. It is not clear, however, how many of the patients, if any, actually had a syncopal attack during the study. If a neurally mediated reflex is to blame , there are a number of potentially responsible receptor sites (carotid, atrial or pul- mon ary baroreceptors). 15c) What advice would you give to this patient about driving? Driving must stop immediately (both his heavy goods vehicle and his car). He must inform th e DVLA of his diagnosis. If asystole is demon- strated on ECG monitoring, he may be conside red fit to drive (HGV and car) once a pacemaker is inserted. If ECG shows no evidence of as ystole, he must not drive until attack-free for 5 years. Cough syncope in HGV drivers has b een reported as causing fatal accidents, with the drivers in each case avoiding prosecution (McCorry and Chadwick 2004). Interestingly this depended on a clear and consistent reporti ng of a char- acteristic history. The precise wording of DVLA advice for conditions relevan t to respiratory and sleep medicine is shown in Table 15.1. Table 15.1 DVLA advice for patients with respiratory conditions Condition Group 1 Entitlement (car, motorcycle) Group 2 Entitlement (LGV/PCV) Sleep disorders (including obstructive sleep apnoea syndrome, causing excessive daytime/awa ke, time sleepiness) Driving must cease until satisfactory control of symptoms has been attained, confirmed by m edical opinion Driving must cease until satisfactory control of symptoms has been attained, with ongoing c ompliance with treatment, confirmed by consultant/specialist opinion. Regular, normally ann ual, licensing review required Cough syncope Driving must cease until liability to attacks has been successfully controlled, confirmed b y medical opinion. Driving must cease. If there is any chronic respiratory condition, including smoking, will need to be free of syncope/pre-syncope for 5 years. Individuals identified as having asysto le in response to coughing can be considered once a pacemaker has been implanted and workin g continued CASE HISTORIES IN RESPIRATORY MEDICINE 124 Table 15.1 DVLA advice for patients with respiratory conditions (continued) Condition Group 1 Entitlement (car, motorcycle) Group 2 Entitlement (LGV/PCV) Carcinoma of lung DVLA need not be notified unless cerebral secondaries are present. Those drivers with non small cell lung cancer classified as T1N0M0 can be considered on an individual basis. In other cases, driving must cease until 2 years has elapsed from the tim e of definitive treatment. Driving may resume, providing treatment is satisfactory and no b rain scan evidence of intracranial metastases Narcolepsy/ cataplexy Cease driving on diagnosis. Driving will be permitted when satisfactory control of symptoms achieved, then 1, 2 or 3-year license with regular medical review Generally considered unfit permanently, but if a long period of control has been establishe d, licensing may be considered on an individual basis Cerebral malignancy (including secondary deposits) Normally, a period of 2 years off driving is required following treatment Permanent refusal or revocation Further reading http://www.dft.gov.uk/dvla/medical/ataglance.aspx (accessed 1st September 2009) Benditt DG , Samniah N , Pham S , Sakaguchi S , Lu F , Lurie KG et al. ( 2005 ). Effect of cough on he art rate and blood pressure in patients with \200\230cough syncope \200\231 . Heart Rhythm ; 2 ( 8 ): 807 \200\223 813 . Irwin RS , Curley FJ , French CL ( 1990 ). The spectrum and frequency of causes, key components of the diagnostic evaluation, and outcome of specific therapy . Am Rev Respir Di s ; 141 : 640 \200\223 647 . Mattle HP , Nirkko AC , Baumgartner RW , Sturzenegger M ( 1995 ). Transient cerebral circulatory arrest coincides with fainting in cough syncope . Neurology ; 45 : 498 \200 \223 501 . Morice AH , McGarvey L , Pavord I ( 2006 ). BTS guidelines: recommendations for the man- agement of cough in adults . Thorax ; 61 ( Supp 1 ): 1 \200\22324. McCorry DJP and Chadwick DW ( 2004 ) Cough syncope in Heavy Goods Vehicle Drivers . Q J Med ; 97 : 631 \200\223 632 . McGarvey LP , Heaney LG , Lawson JT et al . ( 1998 ). Evaluation and outcome of patients wi th chronic non-productive cough using a comprehensive diagnostic protocol . Thorax ; 53 : 7 38 \200\223 743 . Santini M , Ammirati F , Colivicchi F , Gentilucci G , Guido V ( 1999 ). The effect of atro pine in vasovagal syncope induced by head-up tilt testing . European Heart Journal ; 20 : 1 745 \200\223 1751. Sharpey-Shafer EP ( 1953 ). The mechanism of syncope after coughing . BMJ ; 2 : 860 \200 \223 863 . Case 16 A 37-year-old woman had several years \200\231 history of slowly progressive breath- lessne ss, and a cough productive of small volumes of sputum. She had obstruc- tive spirometry (FE V 1 1.06L, 36% of predicted, and FEV 1 /FVC ratio 38%) with no reversibility (FEV 1 improve ment less than 15% after nebulized salb- utamol). She had been on maximal therapy for asthm a for several years. She was a smoker with an 18-pack year history, and worked as a shop as sistant. Her father had died in his 50s from a respiratory condition. Fig. 16.1 CXR. Questions 16a) What does her CXR show (Fig. 16.1)? 16b) Suggest the most likely cause for this lady \200\231s presentation, and some less likely alternatives that should be considered. 16c) Discuss the single investigation that could be carried out to diagnose the most likely condition. CASE HISTORIES IN RESPIRATORY MEDICINE 126 Answers 16a) What does her CXR show (Fig. 16.1)? Her CXR show hyperinflated lung fields with flattened diaphragms. There is increased basal lucency. 16b) Suggest the most likely cause for this lady \200\231s presentation, and some less likely alternatives that should be considered. Causes of fixed airflow obstruction. This young lady is a smoker with fixed airflow obstruc tion, as illustrated by spirometry and CXR. With onset at this early age, a likely diagnosi s is alpha-1 antitrypsin deficiency. Other diagnoses that could be considered are: \227\206 Obliterative bronchiolitis (previous history of organizing pneumonia or a connective tissue disorder?) \227\206 Chronic asthma with chronic sub-optimal control (causing airways remodeling and loss of reversibility) \227\206 COPD with increased risk-factor exposure (very early age of starting smoking? Occ upational exposure? Concomitant cannabis smoking?) \227\206 Upper airway obstruction due to a thyroid goiter or tumor, although the history o f several years makes a tumor less likely (do airflow loops show predominant inspiratory ai rflow limitation?) 16c) Discuss the single investigation that could be carried out to diagnose the most likely condition. A single investigation to diagnose alpha-1 antitrypsin deficiency is blood alpha-1 antitryp sin levels: normal range 20 \200\22352 mol/L (1.5 \200\2233.0g/L). The patient in this case had serum alpha-1 antitrypsin levels of 2.4 mol/L (0.2g/L), well b elow both the normal range and the protective threshold of 35% of the normal mean value ( \211 11 mol/L or \211 0.8g/L). Above this level, pulmonary symptoms tend not to occur. Her C-reactive protein (CRP), measured simultaneously, was not high. This is important as alph a-1 antitrypsin is an acute phase protein and can transiently increase, thus the test shoul d be repeated if the CRP is high. CASE 16 127 Questions 16d) What general pointers increase the likelihood of alpha-1 antitrypsin deficiency? 16e) Discuss the genetic basis of this condition. 16f) What is the mechanism of liver and lung disease in alpha-1 antitrypsin deficiency? 16g) What advice should this patient be given? 16h) What monitoring should she have? CASE HISTORIES IN RESPIRATORY MEDICINE 128 Answers 16d) What general pointers increase the likelihood of alpha-1 antitrypsin deficiency? Pointers suggesting the possibility of alpha-1 antitrypsin deficiency: \227\206 Pulmonary emphysema in a young adult (<45y) \227\206 Pulmonary emphysema with a modest smoking history or little expo- sure to dust or high concentrations of airborne particles \227\206 Pulmonary emphysema, predominantly in the lower lobes \227\206 Chronic hepatitis without another explanation \227\206 Family members with pulmonary disease or ancestors with pulmonary emphysema in yo ung adulthood, bronchiectasis or liver cirrhosis. 16e) Discuss the genetic basis of this condition. Genetic basis of alpha-1 antitrypsin deficiency. The patient in this case was found to be h omozygous for alpha-1 antitrypsin deficiency, ZZ. \227\206 Inheritance: autosomal co-dominant \227\206 Incidence: 1 in 2000 \200\2235000 (although significantly under-recognized) \227\206 Gene: encoded by the SERPINA1 gene (formerly known as Pi), con- taining more than 100 allelic variants \227\206 Classification: by the effects on serum levels of alpha-1 antitrypsin protein: M alleles are normal variants, associated with normal alpha-1 anti- trypsin levels; constit ute 95% of those found in Caucasians S alleles in homozygous form are associated with plasma alpha-1 antitrypsin levels of 60% n ormal, and are more frequent in the Mediterranean area Z alleles in homozygous form are associated with plasma alpha-1 antitrypsin levels of 10 \200\22315% normal, and account for 95% of cases of severe deficiency The null allele is associated with no detectable circulating alpha-1 antitrypsin, and is ve ry rare Heterozygotes with MS or MZ alleles have modestly reduced alpha-1 antitrypsin levels, but a re not usually symptomatic. \227\206 Gene frequency: alpha-1 antitrypsin deficiency is one of the most com- mon geneti c disorders to affect the white population, with 8% of Northern Europeans and 25% of the po pulation of the Iberian Peninsula carrying an S- or Z- allele for alpha-1 antitrypsin. This has CASE 16 129 led to speculation regarding a possible survival benefit. It has been pos- tulated that, in the pre-antibiotic era, amplified inflammatory response might limit invasive respiratory a nd gastro-intestinal infection; since the availability of antibiotics, and widespread uptak e of smoking, the pro-inflammatory properties of alpha-1 antitrypsin deficiency have on bal ance become detrimental. 16f) What is the mechanism of liver and lung disease in alpha-1 antitrypsin deficiency? Alpha-1 antitrypsin is the antiprotease in the lung present in the highest concentration. I t inactivates proteolytic enzymes in pulmonary tissue, most importantly neutrophil elastase in a ratio of 1:1, for which is has the highest affinity. Proteases are released into lung tissue during phagocy- tosis of airbourne pathogens. Without adequate clearance, such as o ccurs in alpha-1 antitrypsin deficiency, they remain active and slowly proceed to destroy t he lung matrix components, alveolar structures and blood vessels. Within a few decades, the progressive destruction results in COPD. In addition to its antiprotease activity, alpha-1 antitrypsin may inhibit immune responses, stimulate tissue repair and matrix production, a nd have antibacterial activities. Mechanism of disease in alpha-1 antitrypsin deficiency in the liver. In the liver in patien ts with the ZZ variant, further processing of alpha-1 antitrypsin protein synthesized in th e rough endoplasmic reticulum of hepatocytes is delayed, so that approximately 85% of synth esized mole- cules polymerize into large conglomerates. These cannot be processed further a nd accumulate in the rough endoplasmic reticulum. Continued accumulation may result in cell injury and later in cell death. Patients have a highly increased risk of liver fibrosis an d cirrhosis. Null variants synthesize no alpha-1 antitrypsin, and therefore have no liver d isease. 16g) What advice should this patient be given? In alpha-1 antitrypsin deficiency, the mean life-expectancy for smokers is 48 \200\22352 ye ars, with disease progressing more quickly whilst smoking. For non-smokers, life-expectancy is nearly normal. She should, there- fore, be advised to stop smoking, and blood relatives advised not to smoke (in particular of course any siblings who will have a 1 in 4 chance o f alpha-1 antitrypsin deficiency for this autosomal recessive condition), with appropriate support offered to achieve this. Genetic counseling is not routinely offered at present, bu t may become indicated if specific therapy is developed in the future. CASE HISTORIES IN RESPIRATORY MEDICINE 130 16h) What monitoring should she have? Disease progression should be monitored with spirometry (or full pulmonary function tests), and liver function tests at intervals (annually is sufficient). Adults with alpha-1 antitr ypsin deficiency develop liver disease less frequently than pulmonary manifestations. Hepat ic symp- toms manifest initially as hepatitis, followed later by fibrosis or cirrhosis. If abnormal liver function tests develop, the patient should be investi- gated further with a liver ultra-sound, screened for other causes of hepatitis or cirrhosis, and specialist hepa tic referral may be appropriate. A small proportion of patients with homozygous deficiency genotypes develop neonatal hepatitis syndrome with cholestasis. This usually resolves after a few weeks, and is not associated with adult liver disease. Patients may be referred to a specialist center; in the UK these are in Birmingham, Edinburgh and Cambridge. Clinical progress Following the diagnosis of alpha-1 antitrypsin deficiency with COPD, she discontinued smoki ng. Over the next 10 years her condition progressively worsened. She had recurrent infectiv e exacerbations and a reduced exercise tolerance, with difficulty climbing hills, and was o nly able to climb half to one flight of stairs. Her FEV 1 was 1.1L (38% of predicted). She was on optimal therapy for COPD, including high-dose inhaled steroids, long- and short-acti ng beta agonists, and tiotropium. She had completed a pulmonary rehabilitation program, and had pneumococcal and influenza vaccinations. A CT-chest of a patient with alpha-1 antitryp sin deficiency (not the patient in this case) is illustrated in Fig. 16.2 . CASE 16 131 (a) (b) Fig. 16.2 CT chest. Questions 16i) What features of alpha-1 antitrypsin deficiency does the CT-scan ( Fig. 16.2 ) illustrate? 16j) What further treatent specific to alpha-1 antitrypsin deficiency may become available in the future? CASE HISTORIES IN RESPIRATORY MEDICINE 132 Answers 16i) What features of alpha-1 antitrypsin deficiency does the CT-scan ( Fig. 16.2 ) illustrate? The CT scan shows predominant basal disease, with pan-acinar emphy- sema. Associated bronch iectasis is commonly seen, although not present in this case. 16j) What further treatment specific to alpha-1 antitrypsin deficiency may become available in t he future? No treatment specific to alpha-1 antitrypsin is currently recommended. At present treatment simply consists of optimization of usual COPD therapies, including smoking cessation, and in severe end-stage disease, consideration of lung transplantation in carefully selected pa tients. \200\230Augmentation therapy \200\231 with alpha-1 antitrypsin supplementation has been tr ialed, with a target serum alpha-1 antitrypsin level of 11 M or greater, since this level protects from development of emphysema. This level was achieved in one trial with weekly in travenous alpha-1 antitrypsin at a dose of 60mg/kg from pooled human plasma, without signif icant adverse events. Subsequent studies have trialed different doses and time intervals. S tudies are inconclusive with some, but not all, showing a modest reduction in rate of decli ne of FEV 1 , one showing a mortality benefit, and another a trend towards slower loss of l ung tissue on CT. Benefits were seen in patients with moderate severity COPD only. A recent 2 -year study (Dirksen et al . 2009) of weekly intra-venous alpha-1 antitrypsin i n 77 patients has shown a significant reduction in exacerbation severity, but only a trend towards reduction in exacerbation frequency and reduced progression of disease on CT of the chest. Augmentation therapy using inhaled alpha-1 antitrypsin has been considered, and demonstrate d to increase concentrations in the epithe- lial lining fluid. Adequate delivery to the per iphery of the lungs and to the interstitium remains a challenge, especially as many patient s with deficiency already have abnormal lungs with heterogeneous ventilation. Augmentation therapy confers no benefit to patients with liver dis- ease, since pathogenesis relates to accumulation of unsecreted alpha-1 antitrypsin within hepatocytes. Trials of other strategies may be undertaken in the future, e.g. use of inhaled recombinant secretory leuko-proteinase inhibitor, gene therapy to transfect airway cells with the alph a-1 antitrypsin gene or strategies to facilitate liver secretion of the Z variant of alpha- 1 antitrypsin by preventing its polymerization or use of chaperone molecules. CASE 16 133 Further reading Abusriwil H , Stockley RA ( 2006 ). Alpha-1 antitrypsin replacement therapy: current status . Curr Opin Pulm Med ; 12 : 125 \200\223 131 . Dirksen A , Piitulainen E , Parr DG , Deng C , Wencker M , Shaker SB et al . ( 2009 ) Explo ring the role of CT densitometry: a randomized study of augmentation therapy in alpha-1 ant itrypsin deficiency . Eur Respir J ; 33 :1345 \200\22353. Heresi GA , Stoller JK ( 2008 ). Augmentation therapy in -1 antitrypsin deficiency . Expe rt Opin Biol Ther ; 8 : 515 \200\223 526 . Kohnlein T , Welte T ( 2008 ). Alpha-1 antitrypsin deficiency: pathogenesis, clinical presentation, diagnosis, and treatment . The Am J of Med ; 121 : 3 \200\223 9 . Lomas DA ( 2006 ). The selective advantage of -1 antitrypsin deficiency . Am J Respir Cri t Care Med ; 173 : 1072 \200\223 1077 . This page intentionally left blank Case 17 A 62-year-old man, with a history of pulmonary sarcoidosis, attended with progressive breat hlessness over the preceding 6 months, such that current exercise tolerance was only 50 yar ds. In addition he had noticed increasing ankle swelling over the last 4 weeks. He denied a ny other respiratory or systemic symptoms and was a non-smoker. His diagnosis of sarcoidosis was made 3 years previously following presenta- tion ( Table 1 7.1 PFT 1) with dyspnoea, and CT findings of diffuse ground glass with ill-defined centrilo bar ground glass nodules. Because the appearances were atypical for sarcoidosis, a surgical lung biopsy was performed, which showed numerous discrete non-caseating granulomas in a pe rivascular and peribronchiolar distribution. There was patchy lymphocytic infiltrate, pauci ty of eosinophils and minimal fibrosis. Overall the appearances favored sarcoidosis over al ternative diagnoses. Following the lung biopsy, he was com- menced on 40mg prednisolone, wh ich improved his breathlessness ( Table 17.1 PFT 2). Over the next 2 years his steroid dose was gradually tapered down to 5mg/day, but when seen at that point ( Table 17.1 PFT 3), th e dose was increased to 20mg as his dyspnoea had worsened. He had remained on this dose unt il he re-presented 9 months later ( Table 17.1 PFT 4). His past medical history included localized prostate carcinoma (treated with radiotherapy a nd hormonal treatment) and a monoclonal gammopathy of unknown significance (MGUS). On exami nation, resting Sa O 2 on air was 88%, there was gross pitting oedema to the knees and the JVP was markedly elevated with prominent V waves. Cardiovascular examination revealed a mar ked right ventricular heave and a loud second heart sound. No murmurs were audible, and res piratory examination was otherwise unremarkable. Investigations \227\206 Hb 15.4g/dL, WCC 8.63 \227 10 9 /L (normal differential), platelets 158 \227 109 /L \227\206 ESR 5mm/h, CRP 17mg/L \227\206 U&E normal \227\206 Bilirubin 27 mol/L, ALT 40IU/L, GT 122IU/L, ALP 318IU/L \227\206 Adjusted calcium 2.37mmol/L, ACE 35IU/L \227\206 PSA <0.1ng/mL \227\206 IgG paraprotein 9.3g/L (measured at 14g/L in 2005) \227\206 IgM 0.13g/L (0.4 \200\2232.5), IgG 14.2g/L (6.0 \200\22313), IgA 1.7g/L (0.8 \200 \2233) \227\206 Urine electrophoresis normal, ANA, RF negative. CASE HISTORIES IN RESPIRATORY MEDICINE 136 Table 17.1 Pulmonary function tests (serial values, with % predicted in parentheses) Date PFT 1 PFT 2 PFT 3 PFT 4 FEV1(L) 3.2 (101) 3.5 3.0 2.5 (81) FVC(L) 4.2 (103) 4.7 4.6 3.9 (99) FEV1/FVC(%) 73 71 65 62 RV(L) 2.2 (90) 2.4 n/a 2.0 (83) TLC(L) 6.2 (97) 6.1 n/a 5.9 (87) VA(L) 5.4 (79) 5.8 6.1 5.5 (81) TLCO(mmol/min/kPa) 4.19 (45) 4.42 3.65 3.38 (37) KCO(mmol/min/kPa/L) 0.78 (57) 0.75 0.6 0.6 (47) Fig. 17.1 CXR. CASE 17 137 Fig. 17.2 ECG. Questions 17a) What alternative diagnoses would have been considered at initial presentation in 2005 based on the radiological and pathological descriptions? 17b) Interpret the lung function tests, CXR (Fig. 17.1) and ECG (Fig. 17.2). 17c) What is the clinical diagnosis and what particular underlying causes should be considered? 17d) Give two key investigations that must now be performed. CASE HISTORIES IN RESPIRATORY MEDICINE 138 Answers 17a) What alternative diagnoses would have been considered at initial presentation in 2005 based on the radiological and pathological descriptions? Hypersensitivity pneumonitis, non- specific interstitial pneumonitis (NSIP) and respiratory bronchiolitis \200\223interstitial lung disease (RBILD). The radiological description of diffuse ground glass opacification with centrilobar ground glass nodules is, along with air trapping on expira- tory CT slices (not seen in our patien t), characteristic of hypersensitivity pneumonitis (HP; see case 8). HP is also a cause of non-caseating granu- lomata on lung biopsy, but the distribution described in the lung biop sy is more in keeping with sarcoidosis. On CT, sarcoid can cause diffuse ground glass but t his is less common than the characteristic parenchy- mal finding of bronchovascular and fis sural nodularity. NSIP can cause diffuse ground glass on CT but granulomas on biopsy are no t a feature (see case 42). RBILD, which causes centrilobular nodules, ground glass opacific ation and also air trapping, could have been considered on radi- ological grounds but this is a disease of smokers. 17b) Interpret the lung function tests, CXR (Fig. 17.1) and ECG (Fig. 17.2). The principle abnormality on lung function testing is a moderate reduc- tion in gas transfe r, which has significantly progressed (>10%) over time. There does appear to have been a re duction in FEV 1 over time, with the development of mild airflow obstruction (which might b e a manifesta- tion of peri-bronchiolar infiltration, although a reticular pattern on HRCT has been shown to correlate best with the degree of airflow obstruc- tion). FVC and static lung volumes have not really changed over the course of the patient \200\231s attendance, w hich would have been expected if worsening fibrosis was the explanation. In sarcoidosis, pa renchymal changes can progress initially without significant changes in FVC. 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.