Start Time + Date: 22:23:33 27/03/2006 Y-axis from 70% to 100% Start of night 100 70 End of night Fig. 21.1 Eight sequential hours of oximetry taken from the sleep study. This page intentionally left blank CASE 21 167 Questions 21a) What treatment would you recommend for this patient? 21b) Would you undertake any further investigations? 21c) What advice would you give to this patient about driving? 21d) What impact will the diagnosis have on continuing employment as an airline pilot for this patient? CASE HISTORIES IN RESPIRATORY MEDICINE 168 Answers 21a) What treatment would you recommend for this patient? Although severe OSA was identified on sleep study, he does not complain of excessive daytim e sleepiness and therefore does not have obstructive sleep apnoea syndrome. This distinctio n is important when deciding upon appropriate treatment, and when providing advice regardin g driving (see answer 21c) and so on. In the absence of excessive sleepiness, as long as there is no reason to think the patient is under-estimating this (corroborative history from partner is invaluable), there is littl e justification for recommending nasal CPAP. The principle reason for instituting CPAP in O SA is for the treat- ment of excessive daytime sleepiness. There is no convincing evidence that treatment with CPAP improves blood pressure control in non-sleepy patients with OSA, o r indeed long-term morbidity or mortality. The patient (and his wife) are principally compl aining of snoring and in the first instance careful enquiry as to potential aggravating fac tors (e.g. smoking, alcohol) should be undertaken. A jaw advancement device may be helpful in improving symptoms of snoring. The patient must be counseled strongly that, if there is any concern about excessive daytim e somnolence in the future, he must be re-assessed. 21b) Would you undertake any further investigations? Further investigation in these circumstances would really depend on your belief as to the p atient \200\231s true level of sleepiness, and whether you would wish to confirm this. Ther e is not a good correlation between severity of OSA and level of sleepiness, but his OSA is severe and the Epworth sleepiness score may be purposely under-estimated if the patient (a nd their partner) fears he will lose his livelihood. In cases where either you do not belie ve the reported level of sleepiness, or you feel the patient needs convincing of their true level of sleepiness, a wakefulness test can help. These tests do not correlate with object ive measures of severity of OSA (e.g. Apnoea-hypopnoea Index or ODI), or with future likeli hood of a driving accident. In this case, however, because of his job as a pilot, objective clarification of his reported lack of sleepiness is recommended (see answer 21d). Level of sleepiness can be more objectively defined by: \227\206 Maintenance of wakefulness test (MWT). The patient is asked to stay awake lying s emi-recumbent for 40 minutes in a quiet and darkened CASE 21 169 room on four occasions throughout the same day at 2-hourly intervals (again with continuous EEG monitoring) and length of time taken to fall asleep is recorded. \227\206 Oxford sleep resistance test (OSLER). A variant of the MWT, except sleep latency is assessed behaviourally without EEG monitoring (and without a technician engaged in conti nuous monitoring of the EEG) and is, therefore, easier to administer. The patient is left s emi-recumbent in a quiet and darkened room for 40 minutes, and is asked to stay awake and p ress a fingerpad in response to a dim light, lit regularly for 1 second in every 3. The num ber of missed responses is recorded, and persistent lack of response (failure to respond fo r 21 seconds, or 7 illuminations) defines sleep onset, recorded by computer. \227\206 Multiple sleep latency test (MSLT). Conversely to the MWT, patients lie in a quie t, dim room and are asked to fall asleep (defined by EEG monitoring) on four or five occasi ons at 2-hourly intervals throughout the day and the time taken to do so is measured. 21c) What advice would you give to this patient about driving? When considering driving, the over-riding principle, from a legal point of view, is that an y patient who drives must take responsibility for being safe to drive. Any driver who falls asleep while driving and causes an accident involving themselves or others is personally l iable and, in the case of fatal incidents, may be charged with causing death by dangerous d riving, potentially receiving a jail sentence. Patients with obstructive sleep apnoea syndr ome must inform the DVLA of their diagnosis and not drive until established on treatment th at has improved their exces- sive daytime sleepiness (see case 15). This patient, however, is adamant he is not sleepy and, therefore, does not need to inform the DVLA of his OSA dia gnosis, as he does not have the syndrome. As long as he remains free of sleepiness, he can drive, but must be counseled strongly that, if the situation changes, he must not drive and be referred for re-assessment. All such patients should be advised not to drive if at all sleepy. 21d) What impact will the diagnosis have on continuing employment as an airline pilot for this patient? He must inform his airline and the Civil Aviation Authority (CAA) of the diagnosis of OSA, but emphasize he does not have OSA syndrome. As with the driving rules, there should be no impact on his continuing to fly, but the CAA will require confirmation of lack of sleepines s by an CASE HISTORIES IN RESPIRATORY MEDICINE 170 objective measure. The same advice applies about needing re-assessment if sleepiness become s a problem. Were the situation different and sleepiness was a problem, a minimum of 6 weeks CPAP treatm ent, accompanied by improved sleepiness (ESS \211 9), is required before the CAA would all ow such a pilot to fly. If there is any doubt then as to the genuine level of sleepiness, a MSLT is advised in cur- rent CAA guidelines, despite its poor ability to predict real life sleepiness and lapses in performance. Further reading http://www.caa.co.uk/docs/49/SRG_MedSleepApnoea.pdf (accessed 1st September 2009) Bennett L S , Stradling JR , Davies RJO ( 1997 ). A behavioral test to assess daytime sleepiness in obstructive sleep apnoea . J Sleep Res ; 6 : 142 \200\223 145 . Stradling JR ( 2008 ). Driving and obstructive sleep apnoea . Thorax ; 63 : 481 \200\223 4 83 . Case 22 A 68-year-old man presented with 2 months of progressive breathlessness on exer- tion and w eight loss of 7kg. He had a past medical history of an anterior myocar- dial infarction 3 m onths previously, and hypertension. He was a retired plumber and had had definite asbestos exposure in the past. He had never smoked. On examination he had an oxygen saturation of 95% on air. There was dullness to percussion with reduced breath sounds audible over the left hemithorax. Investigations \227\206 Hb 14.3g/dL, WCC 10.7 \227 10 9 /L, platelets 350 \227 10 9 /L \227\206 CRP 55 mg/L \227\206 U&E, LFT normal \227\206 Pleural aspiration: Serosanguineous fluid Protein 51g/L, lactate dehydrogenase 869IU/L, glucose 3.5mmol/L, pH 7.27 Cytology negative No growth on culture CXR shown in Fig. 22.1. Fig. 22.1 CXR on presentation: large left pleural effusion. Questions 22a) What are the differential diagnoses? 23b) What investigations would you perform next? CASE HISTORIES IN RESPIRATORY MEDICINE 172 Answers 22a) What are the differential diagnoses? Progressive breathlessness with a large pleural effusion is associated with many respirator y, and systemic, conditions. Measurement of protein and lactate dehydrogenase (LDH) should be requested on all initial pleu- ral fluid aspirates, as determining whether the fluid is an exudate or a transudate usually further aids diagnosis (see Table 22.1 ). Table 22.1 Causes of pleural effusion Transudates Exudates Common Common Left ventricular failure Parapneumonic effusion and empyema Liver cirrhosis \200\230hepatic hydrothorax \200\231 Malignancy Hypoalbuminaemia Tuberculosis Peritoneal dialysis Rheumatoid arthritis Nephrotic syndrome Less common Pulmonary infarction Less common Hypothyroidism SLE Mitral stenosis Other autoimmune diseases Pulmonary embolism (10 \200\22320% transudates) Benign asbestos-related pleural effusion (BAPE) Constrictive pericarditis Pancreatitis Urinothorax Post-cardiac injury syndrome (Dressler \200\231s) Meigs \200\231 syndrome Post-coronary artery bypass grafting Superior vena cava obstruction Hepatic/splenic/subphrenic abscess Malignancy (up to 5% are transudates) Oesophageal rupture Rare Ovarian hyperstimulation syndrome (may also be transudative) Yellow nail syndrome Chylothorax Drugs Sarcoidosis Fungal infections CASE 22 173 In clinical practice, pleural fluid protein levels >35g/L represent an exu- date, and <25g/ L a transudate (if the patient has a normal serum protein concentration). However, Light \200\231s criteria can be applied in patients with intermediate protein values (i.e. 25 \200\22335g/L or abnormal serum protein); if any of the following criteria are met the flui d is an exudate: \227\206 Pleural fluid to serum protein ratio >0.5 \227\206 Pleural fluid to serum LDH ratio >0.6 \227\206 Pleural fluid LDH >2/3 the upper limit of normal serum LDH. Caution should be taken, particularly with effusions in patients on diu- retic therapy for heart failure, as although the underlying fluid is formed as a transudate, diuretics may re sult in an exudate on biochemical analy- sis through water removal (i.e. false-positives). In this case, the pleural effusion was an exudate and the management strategy should focus on determining a cause from the list in Table 22.1 . Pleural effusions occur in up to 60% o f patients with pneumonia. Clinically they represent a spectrum from (1) \200\230simple \200\231 parapneumonic effusion (reactive, sterile pleural fluid) to (2) \200\230complicat ed \200\231 parapneumonic effu- sion, with infected pleural fluid resulting in pleural flui d pH <7.2 and fibrinous septations, to (3) empyema \200\224frank pus in the pleural space ( or culture positive). In this case there were no clinical symptoms to suggest pleural infec tion, although these may not always be present, and an infective etiology for his effusion is unlikely. Malignant pleural effusions are responsible for approximately 22% of all pleural effusions. The progressive symptoms and weight loss raise concern of underlying malignancy including mesothelioma given his docu- mented asbestos exposure. Pleural effusions resulting from pulmonary emboli are typically small. In this case, the pr e-test probability was low and few other clinical features (pleuritic chest pain or hypoxia ) suggest this as a cause. Dressler \200\231s syndrome (post-cardiac injury syndrome) is uncommon but should be consid ered. It usually arises 3 \200\22310 weeks after an acute myocardial infarction and present s with fever and pleuritic chest pain. Pleural effusions are commonly unilateral but may ap pear bilaterally. They result from an immunologically mediated reaction and a prompt respon se is seen with non-steroidal anti-inflammatory agents (NSAIDs) or corticosteroid treatment . Drug-induced effusions should be considered and suspected culprits can be checked at: www.p neumotox.com (accessed 1st September 2009). CASE HISTORIES IN RESPIRATORY MEDICINE 174 22b) What investigations would you perform next? Next investigations: (i) Thoracic CT with pleural phase enhancement would be an appro- priate next investigation . In this case the CT appearances ( Fig. 22.2 ) demonstrate a large pleural effusion with a rim of pleural thickening (arrows). These features suggest underlying malignant disease. C T can reliably differentiate benign from malignant pleural disease. Nodular (specificity 94 %), circumferential (specificity 100%) pleu- ral thickening with mediastinal extension (spe cificity 88%) and thickness >1cm (specificity 94%) are all characteristics of pleural malig nancy, but not of the particular tumor type. (ii) Cytological analysis of pleural fluid confirms the diagnosis of malig- nancy in 60% of cases. Analysis of a second sample may improve this rate by 27%, but further thoracenteses are not recommended. In this case, cytological diagnosis was not achieved. Pleural tissue for histo- logical analysis should be obtained. Options include (1) imaging- guided pleural biopsy or (2) thoracoscopic biopsy, diagnostic sensitivity of malignancy is similar with b oth techniques. Blind pleural biopsy (i.e. Abram \200\231s) is not recommended for suspecte d malignant pleural disease (sensitivity 47% vs 87% with CT-guided biopsy technique in pati ents with definite pleural thickening). Fig. 22.2 CT chest. CASE 22 175 Progress Pleural biopsies performed under local anesthetic thoracoscopy confirmed epithelioid malign ant mesothelioma. Questions 22c) What treatment options would you consider at this stage? 22d) What advice would you give the patient and his family regarding compensation and benefit claims? 22e) What is the prognosis? CASE HISTORIES IN RESPIRATORY MEDICINE 176 Answers 22c) What treatment options would you consider at this stage? Management of the patient with mesothelioma requires a multi-disciplinary approach and cons ideration of the following: \227\206 Control of pleural effusion. Drainage of pleural fluid provides effective short-term symptomatic relief for most patient s, but no data exist to predict which, or how quickly, effusions will recur (some reports, for all causes of malignant effusions, suggest up to 100% at 1 month, others a lower rate). Early definitive pleural intervention is, therefore, appropriate to reduce fluid re-accumu lation, with fluid drainage and talc pleurodesis, either thoracoscopically or via a chest t ube (success rate 60 \200\22390%). In some patients the lung fails to re-expand as a result of visceral tumor encasement ( \200\230trapped lung \200\231) and, as pleural symphysis is not possible in this group, attempts at pleurodesis is not recommended. Repeated pleural a spiration can be performed if symptoms persist and are relieved by fluid evacuation (this i s also appropriate for patients in whom pleurodesis is unsuccessful). Insertion of an indwe lling pleural catheter should be considered, if symptomatic pleural fluid re-accumulation n ecessitates continued repeat aspirations or hospital admissions, in patients with a reasona ble performance status. \227\206 Radiotherapy. Mesothelioma has a tendency to metastasize along tracts of previous pleural puncture sites. Prophylactic drain site radiotherapy has previ- ously been shown to reduce tract spread bu t this finding was not con- firmed in two recent randomized controlled trials. Its benefit remains a topic of debate. Radiotherapy is effective in treating tract metastases if they d evelop. \227\206 Chemotherapy. The anti-folate drugs, pemetrexed (Alimta) and raltitrexed, in combi- nation with cisplatin have been shown to improve life-expectancy (in the EMPHACIS trial, n = 448, median surviva l increased from 9.3 to 12.1 months with combination treatment compared to cisplatin alone ( P = 0.02)). Although data are limited, single-agent pemetrexed has demonstrated promising activity in both chemo-na ve mesotheli- oma patients, and as a second line agent. CASE 22 177 \227\206 Surgery. No quality evidence supports the use of radical surgery (extrapleural pneumonectomy, EPP) a nd this does not improve survival. It carries a high mortality (5 \200\22310%) and morbidit y (25% life-threatening post- operative complications), and has recently been shown to sign ificantly impair quality of life for at least 6 months post-operatively. The role of tri-mo dality treatment with EPP, adjuvant radiotherapy and chemo- therapy is under investigation. Large retrospective series have shown a worse prognosis for patients who underwent EPP, th an for those who had pleurectomy/decortication (PD). A randomized trial on PD vs talc pleur odesis alone is underway. \227\206 Psychological support. Involvement of the multi-disciplinary team is paramount to support patients and their carer s. Patients with mesothelioma have unique psycho-social issues, such as the possible future need for a coroner \200\231s post-mortem, medico-legal aspects regarding compensation, spe cific fears of a \200\230horrible death \200\231 and resentment towards previous employers for lack of occupational protection. \227\206 Pain control (see question 22f). Pain is a common symptom and regular analgesia is often required. Targeted radiotherapy can ease pain, e.g. from bone erosion or tract metastases. Percutaneous cervical cordotomy (in terrupting the spi- nothalamic tract at C1-C2), application of intrathecal analgesia, or re gional nerve blocks may be considered. \227\206 Other. Anorexia and weight loss may be significant, and maintenance of a high-calorie diet should be advised. Oral corticosteroids may improve patients \200\231 appetite and sense of well-b eing. Complementary therapies, counseling and psychology input may help reduce feelings of anxiety and shock. Troublesome cough may ease with pleural effusion drain- age (see above), and use of a codeine, or simple linctus or oral opiate treatments, can be tried. Excessive sweating may be relieved using anti-pyretics, steroid therapy and anticholinergic agents. There is some evidence supporting thalidomide (by reducing cytokine pro- duction) but this should currently be for specialist use only. 22d) What advice would you give the patient and his family regarding com- pensation and benefit claims? Application for compensation claims and benefit entitlements for asbestos-related disease c an result in additional anxieties. Claims can be CASE HISTORIES IN RESPIRATORY MEDICINE 178 made for mesothelioma, asbestosis and diffuse pleural thickening; how- ever, a recent rulin g by the Court of Appeal (October 2007) has vetoed the rights of patients with pleural plaq ues to claim compensation. It is worth involving a specialist solicitor early on, as direct evidence from the sufferer is valuable and more reliable than indirect recollections from the patient \200\231s next of kin. For patients with mesothelioma, eligibility for compensation depends on demonstrating a cle ar history of occupational asbestos exposure. Patients should be given time to construct a detailed employment history, including companies worked for, duration and method of exposur e, and any documentation (e.g. P60s, payslips) from the period of employment. The contact d etails of old colleagues who have also developed asbestos- related disease may be useful du ring the compensation process and allow corroboration of the exposure history. Compensation claims may be sought from two main sources: 1. From the Government (Department of Work and Pensions (DWP), previously the DSS, 0800 882200). (a) Patients can apply for industrial injuries disablement benefit (IIDB) and are eligible for lump-sum payment (state compensa- tion) under the Pneumoconiosis, etc. (workers \200 \231 compensation) Act, but only if the IIDB claim is successful and they have not received payment via a common law action (see below). If the patient is ineligible for Pneumoconiosis, etc. Act (workers \200\231) com- pensation they may be able to claim a one-off lump sum payment under the 2008 Diffuse Mesothelioma S cheme. This scheme covers people whose exposure to asbestos occurred in the United Kingdom and was not as a result of their work as an employee (e.g. those who were self-employed or had indirect exposure (i.e. via a relative or environmentally), or those who cannot trace t heir exposure). (b) If contact with asbestos was made when in the armed forces, a claim may be made via the war pension scheme. This is instead of industrial injuries disablement benefit (Veterans \200\231 Agency Helpline 08001692277) 2. Through the courts via common law (civil) proceedings against a previous employer. If th e employer is still trading and/or the insurers are solvent, an experienced solicitor shoul d be contacted. The Law Society (0870 6066575) or asbestos support groups (available via ww w.mesothelioma.uk.com, accessed 1st September 2009 ) have lists of specialist solicitors. I f the former employers no longer exist, action may be taken provided the insurance company can be traced. CASE 22 179 If the solicitor cannot find the employers or their insurers, patients may still be entitle d to a lump sum payment under the Pneumoconiosis etc. Act (as above) . If patients have been solel y self-employed, they are ineligible for benefit. This is uncom mon and often a civil claim may be made through those with whom they were sub-contracted or did an apprenticeship with (although this would not assist entitlement to IIDB). A 3-year \200\230statutory period from awareness of any asbestos-related disease \200\231 (including pleural plaques) exists for making a claim, although this \200\230limitation pe riod \200\231 is not always strictly enforced. Dependants of the patient may also take legal action to claim compen- sation. This can be i nitiated after the sufferer \200\231s death but must be done within 3 years. Accurate detai ls of employment exposures can be difficult to obtain posthumously. 22e) What is the prognosis? The prognosis of mesothelioma is poor with a median survival of approximately 9 months (alt hough there are a small number of long term survivors >5 years). Adverse prognostic factors include: \227\206 Non-epithelioid (i.e. sarcomatoid or biphasic) histological subtype \227\206 Poor performance status. Weaker predictive factors of a poor outcome include: \227\206 Presence of chest pain \227\206 Age >75 years \227\206 Male sex \227\206 Elevated LDH, white cell and platelet counts \227\206 Anemia \227\206 Weight loss. Progress Five months later the patient was seen in clinic and reported increasingly severe diffuse \200\230gnawing \200\231 left-sided chest pain, particularly at night. He was taking regula r paracetamol and codeine with little relief. Question 22f) How would you address this patient \200\231s pain? CASE HISTORIES IN RESPIRATORY MEDICINE 180 Answer 22f) How would you address this patient \200\231s pain? Pain may be secondary to diffuse pleural involvement, somatic pain (e.g. chest wall invasion) or neuropathic pain (e.g. intercostal nerve involve- ment). In this case, a repeat CT would assess disease progression. Options for pain relief include: \227\206 Early use of opiate analgesia \200\224rapid-dose escalation may be required \227\206 Addition of NSAIDs \227\206 Anticonvulsants (e.g. gabapentin, carbamazepine, sodium valproate) for neuropathic pain \227\206 Radiotherapy for localized chest-wall pain (e.g. bony erosion, tract metastases) \227\206 Percutaneous cervical cordotomy (interrupting the spinothalamic tract at C1/2 ind uces contralateral loss of pain sensation) performed in a specialist center, has a low comp lication rate but patients should be warned about the risks of thermoanaesthesia, post-cord otomy dysaesthesia and unilateral motor weakness \227\206 Use of cingulotomy for relief of refractory pain may be considered in selected patients, but is not easily available. Further reading Boutin C , Rey F , Viallat JR ( 1995 ). Prevention of malignant seeding after invasive diagnostic procedures in patients with pleural mesothelioma. A randomized trial of local ra diotherapy . Chest ; 108 : 754 \200\223 758 . Garcia LW , Ducatman BS , Wang HH ( 1994 ). The value of multiple fluid specimens in the cytological diagnosis of malignancy . Mod Pathol ; 7 : 665 \200\223 668 . O \200\230Rourke N , Garcia JC , Paul J , Lawless C , McMenemin R , Hill J ( 2007 ). A rand omized controlled trial of intervention site radiotherapy in malignant pleural mesothelioma . Radi other Oncol ; 84 : 18 \200\223 22 . Robinson BWS , Lake RA ( 2005 ). Advances in malignant mesothelioma . Lancet ; 353 : 1591 \200\223 1603 . Vogelzang NJ , Rusthoven JJ , Symanowski J , Denham C , Kaukel E , Ruffie P et al . ( 2003 ). Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in pa tients with malignant pleural mesothelioma . J Clin Oncol ; 21 : 2636 \200\223 2644 . Case 23 An 88-year-old woman was admitted with a 6-month history of progressive shortness of breath , a cough productive of small volumes of clear sputum and lethargy. In the preceding 3 week s her symptoms had worsened, also with epi- sodes of feeling hot and shivery. Three courses of antibiotics from her GP had not improved symptoms. She had previously been given a diag nosis of late onset asthma, on the basis of several year \200\231s history of shortness of breath and wheezing at night, worse in the springtime and with exposure to oil seed rape. S he had no other atopic history. Symptoms had improved a little with inhaled beclomethasone 200 g, two puffs twice daily and salbutamol, as required. She was an ex-smoker with a 10-p ack year history. She had a past medical history of hypertension, palpitations, congenital double uterus and absence of right kidney, recurrent cystitis, previous cholecys- tectomy, Herpes zoster infe ction and irritable bowel syndrome. Her long-term medications included diltiazem, furosemid e, nitrofurantoin, omeprazole and mebeverin. On examination she was dyspnoeic at rest, with a heart rate of 110 and respiratory rate of 32. She had bilateral inspiratory crackles, but no wheeze and no signs of fluid overload. O xygen saturations were 89% on air. Investigations \227\206 Hemoglobin, 12.3g/dL \227\206 White cell count, 14.1 \227 10 9 /L \227\206 Neu trophils, 9.6 \227 10 9 /L \227\206 Eosinophils, 1.1 \227 10 9 /L \227\206 Platelets, 5 60 \227 10 9 /L \227\206 U&E normal \227\206 CRP, 58mg/L \227\206 D-dimer, 1532 g/L (normal range <500) \227\206 Troponin <0.02 (negative) \227\206 Aspergillus (IgG), 1 precipitin line \227\206 Aspergillus (IgE), <0.35kU/L (negative) \227\206 Total IgE, 120kU/L (5 \200\223120) \227\206 Anti-nuclear antibodies, 160 titre (0 \200\22380) \227\206 ANCA negative \227\206 Rheumatoid factor <9.5IU/ml (negative) CASE HISTORIES IN RESPIRATORY MEDICINE 182 \227\206 ECG: sinus tachycardia, with normal axis, no ischaemic changes and first-degree heart block. \227\206 Arterial blood gas on 28% FiO 2 pH PaCO 2 PaO 2 SaO 2 Base excess 7.47 4.5 kPa 11.2 kPa 97% 1.0 mmol/L Bicarbonate 26 mmol/L \227\206 FEV 1 /FVC ratio 83%. Fig. 23.1 CXR. CASE 23 183 Questions 23a) Discuss potential causes of this lady \200\231s shortness of breath, with evidence for and against each. 23b) What step is important to try and halt the progression of her underlying condition? CASE HISTORIES IN RESPIRATORY MEDICINE 184 Answers 23a) Discuss potential causes of this lady \200\231s shortness of breath, with evidence for and against each. Possible contributors to her shortness of breath: \227\206 Usual interstitial pneumonitis (UIP). This lady \200\231s history of shortness of breath, inspiratory crackles, restrictive spirometry, raised CRP and antinuclear antibodie s, and infiltrates on CXR are in keeping with UIP. The deterioration over the preceding 3 w eeks could have been caused by an accelerated phase of UIP, or by a co-existent condition, such as one of those listed below. \227\206 Lower respiratory tract infection. An acute deterioration over 3 weeks may repres ent an infective cause. In support of this she had felt fever- ish, with raise acute inflam matory markers. The CXR is markedly abnormal, with reticular infiltrates and left basal opa cification. \227\206 Left ventricular failure. In support of this diagnosis she has cardiac risk facto rs (hypertension and a possible dysrhythmia); however, her ECG does not show acute ischaemi c changes, and although the CXR shows an increased cardio-thoracic ratio, there are no Kerl ey-B lines or fluid in the lateral fissure to suggest heart failure. \227\206 Pulmonary embolus. Several tests would support a diagnosis of pulmonary embolus, however, there are more likely causes for each of them. D-dimer is an acute-phase reactant, and so an elevated level is not necessarily indicative of thrombo-embolic disease in the p resence of infection or an inflammatory disorder. She has a widened alveolar \200\224 arter ial PO 2 gradient (PO 2 only 11.2kPa despite 28% inspired oxygen fraction); however, the pr esence of inspiratory crackles and CXR changes means there are other potential causes for t his. The risk of pulmonary embolism is increased in congestive cardiac failure and chronic obstructive pulmonary disease in stable patients, and even more so during acute exacerbatio ns. \227\206 Chronic nitrofurantoin induced lung disease. This lady had been on long-term nitr ofurantoin and her presentation, with insidious short- ness of breath over months, is in ke eping with nitrofurantoin-induced lung disease. In particular she has: Pulmonary infiltrates and fibrosis (right hemithorax volume loss, with tracheal deviation to the right, and reticular shadowing) Eosinophilia (count 1.1 \227 10 9 /L) \227\217 Bronchospasm (previously diagnosed as \200\230late onset asthma \200\231) Positive antinuclear antibody: a drug-induced lupus. CASE 23 185 Other pulmonary complications of nitrofurantoin are listed at www. pneumotox.com, and inclu de ; \227\206 Acute nitrofurantoin-induced lung disease which usually has an abrupt onset withi n 3 weeks of starting the drug with fevers, chills, cough, dyspnoea, abnormal CXR, leucocyt osis and eosinophilia. It usually resolves after the drug is discontinued. \227\206 Subacute nitrofurantoin-induced lung disease, associated with an eosinophilia, vasculitis and hypersensitivity. \227\206 Chronic nitrofurantoin-induced lung disease, which much less common, and is chara cterized by increasing dyspnoea on exertion, dry cough, bilateral diffuse infiltrates and f ibrosis, more prominent at the lung bases, often with a pleural effusion. It is not clear what phase of the disease our patient was in, as she has features of each. The acute and chronic forms of lung injury result from different pathogenic mechanisms. The acute form is a hypersensitivity reaction (type I or III). The chronic form may be either an allergic or a toxic response. Theoretically, hyperoxia accelerates toxicity, and antioxi - dants protect from toxicity through cyclic oxidation and reduction. This mechanism of lun g damage may be similar to that observed with the herbicide paraquat. Nitrofurantoin-induced lung disease is not a dose-related phenomenon, and the incidence is higher in women, simply because they are more prone to urinary tract infections and, theref ore, receive more treatment with nitrofurantoin. One study has found the incidence of hospi taliza- tion following a single prescription to be just under 1 in 5000, and of 742 people with >10 prescriptions of nitrofurantoin, there was one fatal case attributable to the drug . Non-pulmonary manifestations of nitrofurantoin include mild gastro-intestinal symptoms, a cute allergic reactions, hepatic, neurological and hematological toxicity. \227\206 Amiodarone-induced lung disease. Amiodarone is one of the com- monest drugs to in duce lung disease, and should be considered in this lady \200\231s case given her history o f dysrhythmias. However, review of her notes documented no amiodarone use. 23b) What step is important to try and halt the progression of her underlying condition? Key management to try and halt disease progression: \227\206 Nitrofurantoin must be discontinued as soon as an adverse drug reac- tion is susp ected. Prognosis depends upon the drug reaction and how soon the complication is recognized and nitrofurantoin withdrawn. CASE HISTORIES IN RESPIRATORY MEDICINE 186 Following an acute reaction, the prognosis is good. Following chronic lung disease, drug wi thdrawal may lead to an improvement; however, mortality is still 10%. The role of corticost eroids in nitrofurantoin- induced lung disease has not been properly evaluated. \227\206 For the suspected UIP component of her disease, drug treatment is not used routin ely. Oral corticosteroids alone, or in combination with azathioprine, may improve lung func tion and survival, though studies supporting their use probably included some patients with pulmonary fibrosis other than UIP, such as non-specific interstitial pneumonitis, which is steroid responsive. Further progress Intra-venous amoxicillin and oral erythromycin were given for a community acquired pneumoni a. Her shortness of breath improved a little, and the CRP fell; inspiratory crackles and CX R changes persisted. A CT was performed ( Fig. 23.2 ). CASE 23 187 Fig. 23.2 CT chest. Questions 23c) Describe the CT chest changes. 23d) What further investigations could be considered? CASE HISTORIES IN RESPIRATORY MEDICINE 188 Answers 23c) Describe the CT chest changes. The CT shows ground glass opacification associated with traction dilata- tion and bronchiec tasis, and areas of coarse reticulation and honey- combing. In the upper zones on CT, chang es predominate on the right. Appearances would be in keeping with severe usual interstitial pneumo- nitis, although the asymmetrical distribution would be unusual. 23d) What further investigations could be considered? An open lung biopsy is sometimes helpful in cases of pulmonary fibrosis where there is doub t regarding the underlying diagnosis. Full pulmonary function tests aid assessment at seque ntial follow-up. This lady was not sufficiently stable to be considered for this. Early recognition of drug toxicity is important as it is a common cause of morbidity and ev en mortality. Unfortunately the lady in this case went on to develop progressive fibrosis a nd secondary pulmonary infection, and died 3 months after initial presentation. Further reading Jick SS , Jick H , Walker AM , Hunter JR ( 1989 ). Hospitalization for pulmonary reactions following nitrofurantoin use . Chest ; 96 : 512 \200\223 515 . Martin WJ ( 1991 ). Pharmacologic and other chemical causes of interstitial lung disease . Chest ; 100 : 231 \200\223 233 . Schattner A , Von der Walde J , Kozak N , Sokolovskaya N , Knobler H ( 1999 ). Nitrofurantoin-induced immune-mediated lung and liver disease . Am J Med Sci ; 317 ( 5 ): 3 36 \200\223 340 . Case 24 A 45-year-old engineer (born 1943) was referred by his GP for possible sleep apnoea in 1988 . His presenting complaint was increasing and severe daytime sleepiness (he had fallen asle ep whilst on the telephone and driving), general tiredness and fatigue, and restless sleep. He was known to be a snorer, but not every night. He had been a smoker for 25 years, havin g given up recently. He had had rheumatic fever aged 6 and a squint operation aged 8. Aged 16 he was 6ft 2in but by 17 he had lost 2in and was noticed to have a scoliosis. By aged 20 this was bad enough to require a spinal fusion. On examination he was 5ft 9in and thin (BM I 21). Apart from the scoliosis there was no evidence of a neuromuscular abnormality, in pa rticular no fasciculation; nor evidence of cor pulmonale. Investigations Formal sleep study (Fig. 24.3) showed that the episodes of worsening hypoxae- mia were duri ng REM sleep, and there was no evidence of obstructive sleep apnoea. Pulmonary junction (Table 24.1) and blood gasses (Table 24.2) were as follows. Table 24.1 Pulmonary function tests % Predicted PEFR(L/m) 375 75 FEV1(L) 1.6 48 FVC(L, standing) 2.2 53 FVC(L, lying) 2.1 51 FEV1/VC(%) 72 low normal FRC(L) 2.3 66 RV(L) 1.4 59 TLC(L) 3.6 53 RV/TLC(%) 38 33 RAW(kPa/L/s) 0.14 (<0.2) SGAW(L/s.kPa) 3.1 normal TLCO(mmol/min/kPa) 5.3 56 KCO(mmol/min/kPa/L) 1.70 115 PiMax(cmH2O) 33 low normal PeMax(cmH2O) 95 normal CASE HISTORIES IN RESPIRATORY MEDICINE 190 Table 24.2 Blood gasses PaO2(kPa) 6.81 SaO2(%) standard [HCO 3]- (mmol/l) Aa gradient (kPa) 88 PaCO2(kPa) 7.65 30.6 pH 7.34 3.6 Fig. 24.1 Chest radiograph. Fig. 24.2 Chest CT slice. CASE 24 191 Eight sequential hours of oximetry \200\223 each line 70 \200\223100% SaO2 Start of night 100 70 End of night 60 minutes Fig. 24.3 Eight sequential hours of oximetry taken from the sleep study. Questions 24a) What abnormalities do the lung function tests show? 24b) What abnormalities do the blood gasses show? 24c) Can the lung function tests explain the blood gasses? 24d) Does the CXR and CT slice help? 24e) Does the sleep study help? 24f) What general group of disorders are these abnormal findings likely to result from? CASE HISTORIES IN RESPIRATORY MEDICINE 192 Answers 24a) What abnormalities do the lung function tests show? Lung function shows a restrictive defect with no evidence of additional airways obstruction . Lung volume measurements are about 50% pre- dicted. The FEV 1 /VC ratio is slightly low; however, there is no evidence of air trapping (normal RV/TLC ratio), increased airways obst ruction or decreased conductance. The KCO is slightly raised, as one would expect if there was failure to expand otherwise relatively normal lung. The pre- served FVC on lying down e ssentially rules out diaphragm weakness. The expiratory mouth pressure is well preserved; t he inspiratory pres- sure is a little low, either due to weak muscles or mechanically disad van- taged muscles, as occurs in scoliosis. 24b) What abnormalities do the blood gasses show? The blood gasses show a partially compensated, mild ventilatory failure with a small increa se in Aa gradient. 24c) Can the lung function tests explain the blood gasses? Lung function and blood gasses. In patients with a scoliosis, the VC usu- ally has to fall to about a liter before ventilatory failure occurs. With neuromuscular causes of ventilator y failure, it has been shown that the lying VC is the most predictive of diurnal CO 2 reten tion, and usually needs to fall to below 25% predicted normal. Thus to be in ventilatory fa ilure with a lying VC over 2L would be very unusual, and requires addi- tional explanation. This might be obesity (but he is thin), additional airways obstruction (e.g. from his smok ing, but the lung function does not support significant airways obstruction) or a neuromusc ular cause of weakness (for which there is no obvious supporting evidence). 24d) Does the CXR and CT slice help? The CXR (Fig. 24.1) shows the expected scoliosis, with the vertebral sta- bilisation applie d to the lumbar area, rather than the thoracic. The CT slice (Fig. 24.2) shows areas of pro bable atelectasis from failure to ade- quately expand parts of the lung, the likely explana tion for the raised Aa gradient. 24e) Does the sleep study help? The sleep study (Fig. 24.3) shows a stable reduction in SaO 2 during non- REM sleep, and ye t further large unstable falls in SaO 2 during REM sleep, but none of the recurrent saw-too th oxygen desaturations typical of obstructive sleep apnoea. This would be typical of any v entilatory failure CASE 24 193 patient, from many different causes, e.g. neuromuscular, COPD, obesity and scoliosis, as he re. 24f) What general group of disorders are these abnormal findings likely to result from? The likely cause is not clear at all, and one is either looking at two unre- lated diagnose s (e.g. an additional brain stem abnormality such as Arnold Chiari malformation), or a rare neurological diagnosis that could cause both a central control abnormality and the late on set scoliosis. Questions