3c) Suggest a unifying diagnosis. Systemic sclerosis. Scleroderma, Raynaud \200\231s phenomenon, oesophageal dysmotility and possible early interstitial lung disease are suggestive of diffuse cutaneous systemic scler osis. Systemic sclerosis is a generalized connective tissue disorder occurring more commonl y in women. CASE 3 17 Question 3d) There are two subsets of systemic sclerosis: limited cutaneous systemic sclerosis and d iffuse cutaneous systemic sclerosis. What features dis- tinguish them? CASE HISTORIES IN RESPIRATORY MEDICINE 18 Answer 3d) There are two subsets of systemic sclerosis: limited cutaneous systemic sclerosis and d iffuse cutaneous systemic sclerosis. What features distin- guish them? See Table 3.2 . Table 3.2 Comparison of the two sub-types of systemic sclerosis Feature Form of cutaneous systemic sclerosis Limited (formerly called CREST syndrome) Diffuse Raynaud \200\231s phenomenon Present for years, and may be severe Occurs within one year of skin changes Skin changes Limited to hands, face, feet and forearms or absent. Late skin calcification and telangiect asia may occur Widespread skin involvement of both trunk and extremities Nails Dilated nail fold capillary loops Nail fold capillary dilatation and capillary destruction Pulmonary changes A significant late incidence of pulmonary hypertension with or without interstitial lung di sease Early and significant incidence of interstitial lung disease Other organ damage A significant late incidence of trigeminal neuralgia and liver disease Early and significant incidence of oliguric renal failure, diffuse gastrointestinal disease and myocardial infarction Antibodies A high incidence of anti- centromere antibody (70 \200\22380% of patients) Anti-Scl-70 (antitopoisomerase I) antibody positive (30% of patients). Presence associated with interstitial lung disease, and general disease activity CASE 3 19 Questions 3e) How should patients be monitored? 3f) Suggest treatment options. CASE HISTORIES IN RESPIRATORY MEDICINE 20 Answers 3e) How should patients be monitored? Patients with systemic sclerosis affecting the heart, lungs or kidneys require specialist a nd multi-disciplinary follow-up, and may need regular pulmo- nary function testing, echocar diography for estimation of pulmonary arterial pressures and renal function tests. Identifi cation of patients at risk is difficult, as the disease may be quiescent for long periods. The decision to start treatment is often difficult, as many patients have limited disease t hat may not progress. Factors prompting initiation of treatment are: \227\206 Deterioration in serial pulmonary function tests or CXR over the last 6 \200\22312 months \227\206 Severe respiratory disease (extensive disease on CT, moderate to severe reduction in TLCO or restrictive ventilatory defect) \227\206 Duration of systemic disease <5 years (especially <2 years) \227\206 Anti-Scl-70 (antitopoisomerase I) antibody positivity \227\206 Prominent ground glass attenuation on HRCT without traction bron- chial dilation or reticulation. 3f) Suggest treatment options. Most randomized clinical trials have been small ( n <40), and, due to the heterogenous natu re of systemic sclerosis, results are difficult to generalize. In view of this, treatment o f patients with severe disease is often based on expert opinion rather than randomized, con trolled trial data. Due to the equivocal clinical benefit, side-effects, cost, inconvenient routes of delivery of some drugs, therapy is often not given to those with mild disease. In interstitial lung disease, intra-venous or oral cyclophosphamide, and low-dose prednisol one are treatments of first choice. These tend to be con- tinued for one year, before conve rting to prednisolone and azathioprine. In pulmonary hypertension, a combination of calcium antagonists, sildenafil and an endothel in receptor antagonist (e.g. bosentan) are often used in combination. Referral of patients with pulmonary hypertension to a specialist center should be made. Calcium channel blockers, such as nifedipine, may be used to treat symptoms of Raynaud \200 \231s phenomenon, although they do not reverse skin changes, and may worsen oesophageal dys motility. An alternative option is topical glycerol trinitrate paste. CASE 3 21 The prostacyclin analogs, e.g. inhaled iloprost, oral beraprost and subcutaneous treprostin il, have been shown to have a beneficial effect on the vascular manifestations of systemic sclerosis, including both pulmo- nary hypertension (associated with significant improvement s in various pulmonary function, 6-minute walk test and dyspnoea index) and Raynaud \200 \231s phenomenon. Monthly dexamethasone injections may also have a modest beneficial effect on pulmonary function tests and frequency of Raynaud \200\231s attacks. Low-dose oral pred nisolone is sometimes used, although high doses tend to be avoided due to the possible risk of renal crisis, a rare complication of scleroderma, through an unknown mecha- nism. Other agents, such as methotrexate, azathioprine, interferons and antioxidants, have not been sh own to have a significant beneficial effect. Further reading Scleroderma lung disease Henness S and Wigley F ( 2007 ). Current drug therapy for scleroderma and secondary Raynaud \200\231s phenomenon: evidence-based review . Curr Opinion Rheum ; 19 : 611 \200 \223 618 . Highland K and Silver R ( 2005 ). New developments in scleroderma interstitial lung disease . Curr Opin Rheumatol ; 17 : 737 \200\223 745 . Latsi P and Wells A ( 2003 ). Evaluation and management of alveolitis and interstitial lung disease . Curr Opin Rheumatol ; 15 : 748 \200\223 755 . Tashkin D , Elashoff R , Clements P et al . ( 2006 ). Cyclophosphamide versus placebo in scleroderma lung disease . N Engl J Med ; 345 : 2655 \200\223 2666 . Supra-normal carbon monoxide transfer factor in restrictive lung disease Hart N , Cramer D , Ward S et al . ( 2002 ). Effect of pattern and severity of respiratory muscle weakness on carbon monoxide gas transfer and lung volumes . Eur Respir J ; 20 : 1 \200\223 7 . Case 4 A 42-year-old Caucasian female was referred with a cough. She had been diagnosed with asthm a 6 years previously on the basis of a recurrent cough, productive of clear or purulent spu tum, and exertional breathlessness; she had no history of wheeze and her peak flow values d id not vary significantly. She had been treated with high-dose inhaled corticosteroids and long acting beta-2 agonists with little benefit, and a course of oral prednisolone was unhelpful. A 3-month trial of p roton pump inhibitor therapy also gave no relief. She did intermittently use topical nasal steroids for sinusitis but had noticed no impact on her cough. She had never smoked. On examination her SaO 2 was 98% on air. She had crackles in both mid- zones on auscultatio n but no wheeze. Her pulmonary function tests are shown in Table 4.1 (NB Patient coughed du ring expiratory maneuvers). Table 4.1 Pulmonary function tests Measured % Predicted PEFR(L/min) 270 85 FEV1(L) 1.4 71 FVC (L) 2.3 75 FEV1/FVC ratio (%) 59 VA(L) 3.6 78 TLCO(mmol/min/kPa) 3.58 55 KCO(mmol/min/kPa/L) 1.01 71 No change following administration of 5mg nebulized salbutamol Her CXR was normal and a thoracic CT was arranged (basal slices, Fig. 4.1). CASE 4 23 Fig. 4.1 HRCT chest. Questions 4a) Describe the lung function test results. 4b) What do the CT images show? 4c) What investigations would you like to do next? CASE HISTORIES IN RESPIRATORY MEDICINE 24 Answers 4a) Describe the lung function test results. Fixed airflow obstruction with reduced diffusion capacity and transfer factor. 4b) What do the CT images show? A typical \200\230tree-in-bud \200\231 appearance (arrow on close up view below) is seen c haracterized by small centrilobar soft tissue nodules connected by a branching linear opaci ty \200\224this represents underlying bronchiolitis (normal (a) (b) Fig. 4.2 (a) particularly good example of \200\230tree-in-bud \200\231 from another patien t, (b) accentuated through a technique called \200\230maximum intensity projection. \200\230healthy \200\231 bronchioles are too small to be visible on CT). The distribution is predominantly sub-pleural. There is also some dilatation and bronchial wall thickening. Table 4.2 Causes of tree-in-bud appearances on CT chest Causal mechanism Examples Infection Bacterial: Staphylococcus aureus, Haemophilus influenzae Mycobacterium tuberculosis, non-tuberculous mycobacteria Fungal Viral, e.g. Cytomegalovirus, RSV Congenital disorder Cystic fibrosis Idiopathic Obliterative bronchiolitis, diffuse panbronchiolitis (DPB) Inhalation Aspiration, toxic fumes Connective tissue disease Rheumatoid arthritis Malignancy Gastric/renal/breast, post-haematopoietic stem cell transplant CASE 4 25 Pathologically the \200\230tree-in-bud \200\231 appearance correlates with intra-luminal e xudate within peripheral airways and bronchiolar wall inflammation (bronchiolitis). There a re multiple causes summarized in Table 4.2 . 4c) What investigations would you like to do next? \227\206 Routine blood tests, including differential white cell count \227\206 Immunoglobulins, autoimmune profile \227\206 Sputum analysis, culture and sensitivity (including three samples for AAFB analysis). Investigations \227\206 Hb 12.2g/dL, MCV 95.0f L, WCC 6.0 \227 10 9 /L (normal differential), platelets 348 x 10 9 /L \227\206 U&Es, LFTs and coagulation tests were normal \227\206 CRP 12mg/L, ESR 24mm/h \227\206 Immunoglobulins normal \227\206 Rheumatoid factor negative \227\206 Sputum, profuse growth of Haemophilus influenzae . Progress Despite 10-day courses of amoxicillin, erythromycin and cefuroxime, her cough persisted and repeat sputum cultures grew profuse amounts of Haemophilus influenzae . Question 4d) What would you do next? CASE HISTORIES IN RESPIRATORY MEDICINE 26 Answer 4d) What would you do next? A prolonged course (e.g. at least 2 months) of an antibiotic to which the organism is susce ptible would be a reasonable next step. In this case, given the recent drug history and poor response to conventional antibiotic do ses, a longer course of low-dose macrolide therapy could be prescribed, based on a recent E uropean study (Poletti et al. 2003). This study described patients with similar clinical an d radiological findings, all of whom cultured Haemophilus influenzae in sputum or bronchoal veolar lavage spec- imens. The authors reported a good response to low-dose macrolides and suggested that this cohort may represent a forme fruste of diffuse panbron- chiolitis (see below) within a Caucasian population. Progress Shortly after starting clarithromycin, the cough resolved and spirometry returned to normal . Three months of therapy was completed and three years later she remains asymptomatic and off all medication. Summary Although bronchiolitis as a consequence of airway infection is recognized, the repeated iso lation of Haemophilus influenzae in individuals with previously normal lung parenchyma is n ot widely reported. Its presence in patients with a productive cough and exertional dyspnoe a should therefore alert physicians to the possibility of bronchiolitis either as (i) a pre cursor to, or a variant of, \200\230typical \200\231 diffuse panbronchiolitis (DPB) in a g enetically distinct population, or (ii) as a consequence of refractory distal airways infec tion. These patients may benefit from a different therapeutic approach with a prolonged cou rse of low-dose macrolides rather than repeated standard antimicrobial treatment. Diffuse panbronchiolitis (DPB) Diffuse panbronchiolitis (DPB) is a distinct form of small airways disease predominantly se en in Asian populations, particularly the Japanese. In con- trast to Haemophilus influenzae related bronchiolitis, no causal factor has been identified although an infective etiology is postulated. An association with HLA-Bw54 is seen, which is specific to East Asians, and is probably required for development of chronic sinus disease associated with DPB rather t han the lung manifestations per se . This HLA type is uncommon in non-Orientals. CASE 4 27 (In Haemophilus influenzae related bronchiolitis, the European forme fruste of DPB, sinus d isease is less commonly found.) DPB is more prevalent in males and non-smokers in their 2nd to 5th decades. Death from progressive respira- tory failure and cor pulmonale occurs with out treatment. Diagnostic criteria for DPB (Ministry of Health and Welfare of Japan) \227\206 Productive cough (often >50mls sputum/day) and breathlessness \227\206 History of chronic paranasal sinusitis \227\206 Bilateral diffuse small nodular shadows on CXR or centrilobar micro- nodules on thoracic CT \227\206 Coarse crackles \227\206 FEV 1 /FVC <70% and PaO 2 <80mmHg \227\206 Titre of co ld agglutinin \211 64. Investigations \227\206 44% of cases culture Haemophilus influenzae in their sputum at presen- tation. Ps eudomonas colonization increases with time (22% on presen- tation, 60% at four years) \227\206 Cold agglutinins may be elevated in the absence of Mycoplasma pneumoniae \227\206 Pulmonary function shows significant airflow obstruction with variable reduction in diffusing capacity \227\206 HRCT findings are distinctive in DPB, but not pathognomonic, and the changes are graded: 1. Nodules <5mm at end of bronchovascular branching structures 2. \200\230Tree-in-bud \200\231 appearance 3. Early bronchiectasis (cystic dilation of nodules) 4. Large cysts and dilated proximal bronchi. Management Early macrolide treatment, e.g. oral erythromycin 400mg or 600mg daily (2nd line: clarithro mycin 200 \200\223400mg or roxithromycin 150 \200\223300mg daily). The ben- efit of macroli des occurs at a minimum inhibitory concentration below that for an antibacterial effect and is supposed to be anti-inflammatory through inhibi- tion of pro-inflammatory cytokines and suppression of neutrophil activity/ production. CASE HISTORIES IN RESPIRATORY MEDICINE 28 Treatment should continue for at least 6 months to 2 years and cease when symptoms have imp roved with no ongoing functional limitation. Resolution of radiological abnormalities often correlates with clinical findings and even the most severe initial HRCT appearances can be expected to improve. The disap- pearance of centrilobar nodules from HRCT may also act as a surrogate indi- cator for timing the discontinuation of treatment. If symptoms persist, o r return, then macrolide treatment should be restarted. Prognosis The prognosis of DPB was poor (33% survival at 10 years), but with use of mac- rolides it i s now >90% at 10 years. Further reading Poletti V , Casoni G , Chilosi M , Zompatori M ( 2006 ). Diffuse panbronchiolitis . Eur Res pir J ; 28 : 862 \200\223 871 . This page intentionally left blank CASE HISTORIES IN RESPIRATORY MEDICINE 30 Case 5 A 51-year-old lady presented to A&E with shortness of breath for several months, much worse over the last 2 days, now with orthopnoea. Because of associated ankle swelling, she had b een treated with diuretics 2 weeks earlier, which produced a 5kg weight loss and some tempo rary improvement in her shortness of breath. She had no associated history of chest pain, p aroxysmal nocturnal dyspnoea, cough or sputum, no significant past medical history, and no personal or family history of lung disease. System review was negative. She had never smoke d, was unemployed and had two children. On examination: \227\206 Tachypnoeic, undistressed, afebrile, obese (BMI, 40kg/m 2 ) \227\206 Pulse 120 a nd regular, with respiratory paradox, BP 157/92mmHg, JVP to earlobes, 3rd heart sound \227\206 Pitting oedema to thighs \227\206 Crackles and wheezes in chest \227\206 SaO 2 58% on air, 99% on high-flow oxygen \227\206 ECG, sinus rhythm, small complexes and poor R wave progression. A diagnosis of congestive cardiac failure, due to silent myocardial ischaemia, was made. Sh e was given diuretics and O 2 . Whilst awaiting a CXR, bloods and an echocardiogram were or ganized. Investigations \227\206 CXR, large heart, small bilateral pleural effusions, clear lung fields \227\206 CRP, 134mg/L, WBC 12.4x10 9 /L, U&Es normal \227\206 Echocardiogram, small pericardial eff usion, normal valves, good LV function, no ASD, right ventricle slightly dilated and hypert rophied, estimated peak pulmonary artery pressure of 60mmHg. Five hours later she was semi-comatose and incontinent of urine. She was haemodynamically s table with a bounding pulse and warm peripheries, blood gasses were done: pH 7.16, PaO 2 32kPa, PaCO 2 17.5kPa, base excess +10mmol/L. CASE 5 31 Questions 5a) What is the evidence that she has been in ventilatory failure for a while? 5b) What is the most likely reason she became semi-comatose? 5c) Suggest some possible reasons for her ventilatory failure. 5d) Explain her fluid overload (cor pulmonale), why is this not \200\230right heart failure \200\231? CASE HISTORIES IN RESPIRATORY MEDICINE 32 Answers 5a) What is the evidence that she has been in ventilatory failure for a while? She has a raised base excess (+10mmol/l), which indicates a metabolic alkalosis. This has p resumably been caused by renal retention of bicarbo- nate to compensate for a chronically r aised PaCO 2 . Base excess values as high as this are very rarely caused by any other mecha nism, such as diuretic therapy, hypokalaemia, or prolonged vomiting. 5b) What is the most likely reason she became semi-comatose? The most likely reason for her semi-comatose state is the respiratory acidosis caused by th e high PaCO 2 , consequent on her having been given too high a concentration of oxygen in t he presence of prior hypercapnic ventilatory failure. 5c) Suggest some possible reasons for her ventilatory failure. Chronic ventilatory failure (and therefore sensitivity to excessive oxygen levels) can have many causes, but the more likely can be classified most simply as follows (*indicates the commonest causes): \227\206 Primary failure of ventilatory drive \200\224a brainstem abnormality, e.g. Arnold Chiari malformation, brainstem stroke, polio, and post-polio syndrome, syringobulbia, Ondi ne \200\231s curse (e.g. PHOX2B gene abnormalities) \227\206 Pump failure due to a weak pump or \200\230bellows \200\231 function neuropathies, e.g. motor neuron disease (especially if diaphragm involved early), isolated bilateral diaphragm paralysis (e.g. brachial neuritis), spinal muscular atrophy, Guillain- Barr myopathies, e.g. acid maltase deficiency, (diaphragm usually involved early), Duchenne mus cular dystrophy, myotonic dystrophy neuromuscular junction, e.g. myasthenia gravis \227\206 Pump failure due to a heavy load lower airways obstruction e.g. COPD, chronic asthma, bronchiolitis obstructive sleep apnoea (OSA, when with co-morbidities) chest wall, e.g. *scoliosis, *obesity. When a patient is found to be in unexpected ventilatory failure, in reality the commonest c auses are indicated with an asterisk* above. There may well be more than one reason with, f or example, a mixture of COPD, obesity and OSA all being present; in fact OSA rarely causes diurnal ven- tilatory failure on its own, but is a potent provoker when combined with CASE 5 33 COPD and/or morbid obesity. Elucidation of the contributing cause(s) is clearly important b efore the correct therapy can be given. 5d) Explain her fluid overload (cor pulmonale), why is this not \200\230right heart failure \200\231? Cor pulmonale. Chronic hypoxia leads to salt and excessive water reten- tion, probably thro ugh increased sympathetic drive to the kidney. Excess fluid is stored in the venous system, and thus leads to a raised JVP and dependant oedema (if there is left ventricular dysfunct ion as well, then pulmonary oedema may also result). In addition, there will be hypoxic pul monary vasoconstriction with a gradual rise in pulmonary artery pressure and right ventricu lar hypertrophy, but no evidence of poor right ventricular function. There is no reduction in cardiac output; in fact there may be a rise due to the vasodilation caused by the raised PaCO 2 (which may also exacerbate movement of water across capillaries, thus exacerbat- in g the oedema). Hence a common term for this situation, right heart failure, is incorrect: a raised JVP does not automatically mean there is right heart failure as it would, for insta nce, after a large pulmonary embo- lus or right sided myocardial infarction. Further progress The patient was resuscitated with non-invasive ventilation administered via a face mask and rapidly regained consciousness. Repeat history revealed no symptoms of muscle weakness or of brachial neuritis (also called neuralgic amyotrophy), where there can be variable involv ement of the brachial plexus nerves (including phrenic nerves) with shoulder pain and somet ime scapular winging (etiology unknown). There was no history of snoring or witnessed apnoe as, although there had been recent sleepiness. The family confirmed that she had never smok ed. Re-examination did not suggest diaphragm weak- ness (no abdominal paradox during inspir ation or sniffing). There was no fasciculation to suggest motor neuron disease. CT scan of the lungs was normal apart from evidence of air trapping. Lung function See Table 5.1 . Table 5.1 Pulmonary function tests Measured Predicted normal Post salbutamol FEV1(L) 0.5 2.4 0.9 VC (L) 1.8 3.0 2.2 FEV1/VC (%) 30 75 41 FRC(L) 4.2 2.6 RV(L) 3.5 1.7 TLC(L) 6.5 4.6 RAW(kPa/L/s) 0.53 <0.2 KCO(mmol/min/kPa/L) 1.51 1.66 Flow volume loops showed no evidence of upper airways obstruction CASE 5 35 Questions 5e) What do the lung function tests show? 5f) What is the likely diagnosis? 5g) Suggest the most useful therapeutic trial. CASE HISTORIES IN RESPIRATORY MEDICINE 36 Answers 5e) What do the lung function test show? The lung function tests show severe airways obstruction with marked air trapping. There is significant reversibility. 5f) What is the likely diagnosis? This pattern would be compatible with asthma, COPD or bronchiolitis; however, the improved FEV 1 , and reduced air trapping (increased VC), following bronchodilators would most favor asthma. The increased TLC would more favor emphysema, but the normal K CO would not. 5g) Suggest the most useful therapeutic trial. A trial of steroids would identify if the airways obstruction was due to asthma, or possibl y bronchiolitis, and define the full extent of its reversibility. Further progress A trial of steroids led to a gradual improvement in lung function and, surpris- ingly, a vi rtual return to normal values. Blood gasses returned to normal with resolution of all signs of cor pulmonale. This improvement was maintained with inhaled steroids and long-acting br onchodilators. An assumed diagnosis of chronic asthma was made and, in retrospect, had been present for some months prior to presentation to A&E. It is very unusual for asthma to present in this way, mimicking the airways obstruction, ve ntilatory failure, and cor pulmonale that is most often due to smoking-induced COPD. Presum ably she had a relatively low hypoxic ventila- tory drive, which, along with significant ob esity (BMI about 40), allowed this unusual presentation with hypercapnia. Large variations in hypoxic ventilatory drives are seen within normal populations. Further reading Chapman S, Robinson G, Stradling J and West S ( 2009 ). Oxford Handbook of Respiratory Medicine , 2 nd edn, chapter 15 and 23 , p. 91 and 201 . Case 6 Case A A 54-year-old Asian man presented to the emergency department with a 3-month history of inc reasing dyspnoea, drenching night sweats and weight loss. This was associated with a dry co ugh and occasional small volume haemoptysis. He was born in Pakistan, moved to the UK 3 yea rs previously and had visited his family in Pakistan 4 months previously. He worked in a re staurant and smoked 20 cigarettes per day. On examination, there was cervical lymphadenopathy and signs of a left pleu- ral effusion. A chest drain was inserted and the effusion drained to dryness. Fig. 6.1 CXR (case A). CASE HISTORIES IN RESPIRATORY MEDICINE 38 Blood results: \227\206 Hb, 10.7g/dL \227\206 WCC, 14.3 \227 10 9 /L \227\206 CRP, 40mg/l \227\206 Electrolytes normal \227\206 Mildly raised Alk phos (275IU/L) \227\206 Other LFTs normal \227\206 Tuberculin skin test, grade II positive \227\206 Sputum, smear negative for AAFBs, blood-stained. Pleural fluid results: \227\206 Protein 43g/dL \227\206 Glucose 5.2mmol/L \227\206 LDH 416 IU/L (normal 150 \200\223220) \227\206 30% lymphocytes \227\206 No bacteria, no mycobacteria on ZN stain. He was started on anti-tuberculosis chemotherapy (rifampicin, isoniazid, pyrazinamide, etha mbutol) pending sputum TB cultures. Four weeks later he was referred to the respiratory dep artment with persistent symptoms and worsening liver function tests (alk phos = 350IU/L, AL T =120IU/L, normal bilirubin). TB cultures were still pending. Case B A 19-year-old Chinese man was referred to the respiratory department with a 3-month history of increasing right-sided chest pain, and a 1-week history of vomiting. He remained physic ally very active with a minor decrease in his exer- cise ability only. He had moved from Ch ina to the UK at the age of 12. CXR revealed a large right-sided pleural effusion. He had v isited his parents in China 1 month previously and had been started on 3 agent TB treatment by a local doctor (rifampicin, isoniazid, pyrazinamide), with which he was continuing, des pite the vomiting. Investigations showed raised inflammatory markers (WCC = 15 \227 10 9 /L, CRP = 58mg/L) an d anemia (Hb = 8.7g/dL). Other blood tests were normal. Tuberculin skin test was grade II p ositive, and pleural fluid results as follows: \227\206 Blood-stained fluid \227\206 Protein 39g/dL CASE 6 39 \227\206 Glucose 4.1mmol/L \227\206 LDH 617IU/L (normal 150 \200\223220) \227\206 40% lymphocytes \227\206 No bacteria, no mycobacteria on ZN stains \227\206 Sputum cultures: pending. Questions 6a) How would you now manage the anti-tuberculosis medications in each of these cases? 6b) Are any further investigations required in each case; if so, which and why? CASE HISTORIES IN RESPIRATORY MEDICINE 40 Answers 6a) How would you now manage the anti-tuberculosis medications in each of these cases? Both of these patients have symptoms or investigations that may be consistent with side-eff ects of anti-tuberculosis therapy (deranged LFTs in case A, and vomiting in case B). Howeve r, some thought should be given to the confidence of the diagnosis of TB, especially in the presence of apparent treatment side-effects. In neither case is there a definitive microbiological diagnosis. Although the tuberculin sk in test is mildly positive, this would be an unusual result in a patient with active TB (on e would expect either no response due to immune suppression, or florid positivity). In addi tion, the pleural fluid characteris- tics are against TB pleuritis (in which one would expe ct a low-normal glucose and lymphocyte predominance \200\224see Case 13) and TB effusions a re not usually blood-stained. Both patients are anemic, which is a common finding in TB; ho wever, in the presence of TB pleuritis alone (an immuno- logical reaction to MTB within the pleural space) this is unusual. Given the insecure diagnosis, and possible treatment complications in both these cases, TB treatment should be stopped until a firm diagnosis is established. If all medications are h alted at the same time, there is little chance of resistant organisms developing. 6b) Are any further investigations required in each case; if so, which and why? Further investigations are required to establish the diagnosis firmly as above. Investigati ons to consider are: \227\206 Further imaging \200\224thoracic CT scan with contrast would be helpful in deline ating any pleural abnormality, and may reveal parenchymal disease consistent with TB, allow ing direction of further investigations (e.g. bron- choscopy). The scan should be performed with some pleural fluid left in situ to improve pleural tissue contrast (i.e. not drained to dryness). \227\206 Obtain pleural tissue \200\224 \200\230blind \200\231 (i.e. non-image guided, e.g . Abram \200\231s) pleural biopsy has a good sensitivity (overall around 80%) in the case o f pleural TB. Thoracoscopy and CT-guided biopsy have a higher sensi- tivity than this and a re the investigations of choice, if other diagnoses (e.g. malignancy) are in the differenti al. \227\206 Immunological tests for TB (e.g. interferon gamma assays \200\224see Case 31). Wh ile these tests are highly sensitive in the diagnosis of latent TB, there is controversy as to their role in the diagnosis of active TB infection. Even if CASE 6 41 the test is strongly positive, no microbiological information and sensi- tivities to anti-t uberculosis drugs are available. Progress Pleural TB was not considered to be a likely diagnosis in either of these two cases for the reasons given above. Both patients went on to have thoracic CT with contrast enhancement, which are shown in Fig. 6.2 . Fig. 6.2 CT chest with contrast in cases A and B. Questions 6c) Interpret the CT images. 6d) What is now the most likely diagnosis in each case, and how would you investigate these patients further? CASE HISTORIES IN RESPIRATORY MEDICINE 42 Answers 6c) Interpret the CT images. Case A There is a pleural effusion associated with nodular irregular areas of pleural thickening, with areas of air within the fluid (indicating loculations and presumed secondary to previo us drainage). The atelectatic lung appears to contain areas of low attenuation, raising the suspicion of a lesion within the lower lobe. Case B There is a large left effusion with areas of enhancement in the posterior thorax. In additi on, there is a separate area anteriorly abutting the pericardium that could represent a loc ule (with a wide septation separating it from the rest of the pleural fluid) or a cystic ma ss. 6d) What is now the most likely diagnosis in each case, and how would you investigate these patients further? In Case A, this is now most likely to represent malignant pleural disease, and is likely to be a lung primary with spread to the pleura (staging it as Fig. 6.3 CASE 6 43 T4 disease under the current TNM classification, in the absence of informa- tion on nodal i nvolvement and distant metastases). Pleural biopsy (by thoracoscopy or CT guidance) is the next best test to achieve a diagnosis. In Case B, the likely diagnosis will depend on further characterization of the possible cys tic mass seen in the anterior thorax. If this area represents highly septated pleural fluid , the differential remains wide (pleural infec- tion, inflammatory disorders, longstanding transudates, malignancy). If, however, a cystic mass is identified, malignancy (e.g. germ c ell tumor in this age group) becomes more likely. The easiest next investigation may theref ore be an ultrasound to characterize the anterior lesion, or an MRI. Given the young age of this patient, and the extent of the disease, he under- went a video-assisted thoracoscopic (VATs) procedure, to achieve accurate macroscopic and histological diagnosis, and to clear the pleural space of fluid and septations. Progress Case A The patient underwent local anesthetic thoracoscopy, which revealed macro- scopic evidence of pleural malignancy. Multiple biopsies were taken and a talc pleurodesis performed to pre vent fluid recurrence. The biopsies showed aden- ocarcinoma of likely lung origin, which wa s considered inoperable (stage IIIb disease), and he therefore proceeded to palliative chem otherapy and survived only a few months. Case B Ultrasound was suggestive of a mass lesion rather than septated fluid in the area abutting the pericardium. The patient underwent VATs, which revealed a cystic mass lesion. Multiple biopsies were taken, and the septated effusion cleared. Biopsies revealed abnormal cells wi th spindle cell morphology, con- sistent with a sarcoma. He went on to receive chemotherapy , and died 7 months later. Case 7 A 32-year-old American woman was referred for investigation of left-sided subcostal pleurit ic chest pain. Four months earlier she had been treated for left lower lobe pneumonia (radi ologically confirmed) requiring two courses of antibiotics (amoxicillin and erythromycin). After this illness the chest pain persisted, and she felt \200\230tired and drained \200 \231. She also reported an intermittent cough, productive of small amounts of \200\230off- white \200\231 sputum, but denied other respiratory symptoms. She had had no haemoptysis, f evers or sweats, anorexia or weight loss. She had a history of a left-sided pneumonia aged 8, and of being \200\230chesty \200\231 until 13; otherwise she had been well. She had nev er smoked, and sel- dom drank alcohol. There were no abnormal physical signs. Her CXRs are shown in Fig. 7.1a and b . Questions 7a) What do the CXRs show? 7b) List potential causes for the ongoing symptoms? 7c) What investigation would you like to do next? CASE 7 45 (a) (b) Fig. 7.1 (a) PA and (b) lateral CXR on presentation. CASE HISTORIES IN RESPIRATORY MEDICINE 46 Answers 7a) What do the CXRs show? Consolidation is seen within the postero-basal segment of the left lower lobe (retro-cardia c opacification) on both the PA and lateral images (see Fig. 7.2 ). Fig. 7.2 Lateral CXR: retro-cardiac area of consolidation circled. 7b) List potential causes for the ongoing symptoms? Potential causes for this patient \200\231s ongoing pleuritic chest pain, intermittent prod uctive cough and radiological non-resolution could be: Common: \227\206 Infection Post-infectious pleurisy usually recedes quickly with antibiotic therapy supplemented with appropriate analgesia. Prolonged post- infective cough is common (especially with viral aet iologies) and can last for months. Ongoing symptoms and non-radiological resolution, following standard anti-microbial therapy , should raise suspicion of atypical pathogens, e.g. Legionella spp., Mycoplasma , Chlamydi a pneumoniae , fungi or mycobacteria \227\206 Malignancy CASE 7 47 \227\206 Suppurative lung disease Underlying bronchiectasis or a lung abscess should be consid- ered although the radiologica l appearances are not typical for the latter. Less common: \227\206 Recurrent gastric aspiration \227\206 Thromboembolic disease (with resultant infarction accounting for the radiological change) \227\206 Cryptogenic organizing pneumonia (COP) \227\206 Eosinophilic lung disease, e.g. eosinophilic pneumonia or allergic bronchopulmona ry aspergillosis (ABPA, usually upper lobe predominant) \227\206 Vasculitis/collagen vascular disease, such as Wegener \200\231s granulomatosis or rheumatoid arthritis \227\206 Congenital abnormality, e.g. bronchogenic cyst, bronchopulmonary sequestration \227\206 Drug-induced lung disease. 7c) What investigation would you like to do next? Contrast-enhanced thoracic CT would be a suitable next investigation in view of the failure of clinical improvement and lack of radiological resolu- tion 8 weeks following appropriat e therapy. Further information She had no history of chronic chest disease, tuberculosis, collagen vascular disease, radia tion exposure, foreign body inhalation or risk factors for acquired immunodeficiency states . Investigations \227\206 Hb 15.2g/dL, MCV 86.5fL, WCC 9.2 \227 10 9 /L (normal differential), platelets 387 \227 10 9 /L \227\206 U&E, LFT, glucose, TFT all normal \227\206 CRP <8mg/L, ESR 10mm/h \227\206 Immunoglobulins, normal \227\206 Antinuclear antibodies and rheumatoid factor, negative CASE HISTORIES IN RESPIRATORY MEDICINE 48 \227\206 Streptococcus pneumoniae and Haemophilus influenzae antibody responses within the normal range \227\206 Sputum culture, no growth \227\206 Full pulmonary function tests, normal. \227\206 Contrast enhanced thoracic CT scan (Fig. 7.3). (a) (b) Fig. 7.3 (a) and (b) Contrast-enhanced CT chest images. CASE 7 49 Questions 7d) What does the CT scan demonstrate? 7e) What is the diagnosis? 7f) What are the treatment options? CASE HISTORIES IN RESPIRATORY MEDICINE 50 Answers 7d) What does the CT scan demonstrate? The magnified CT image in Fig. 7.4a demonstrates heterogeneous consolidation within the lef t base sharing an irregular border with the neighboring lung parenchyma. Cystic components are evident and an anomalous vessel is present within the mass (arrow). In the CT ( Fig. 7.4b ), this vessel can be seen as it originates from the aorta (arrow) an d (images not shown) leads directly into the lesion. The lungs are otherwise normal. (a) (b) Fig. 7.4 (a), (b) 7e) What is the diagnosis? These findings are in keeping with a diagnosis of intralobar sequestration (ILS). Pulmonary sequestration is rare and accounts for 0.15 \200\2236.4% of all congenital pulmon ary malformations. It is characterized by the presence of a segment of lung that has no ide ntifiable contact with the normal bronchial tree and derives its blood supply from an anoma lous systemic artery. Two types are recognized: intralobar (ILS) and extralobar seques- tra tion (ELS). Table 7.1 summarizes the main clinical differences. \227\206 Other congenital anomalies (e.g. diaphragmatic hernias, congenital cystic adenoma toid malformation type (CCAM) II and cardiopulmo- nary disease) are seen in 10 \200\22314% of those with intralobar and 50% of those with extralobar sequestration. \227\206 The exact etiology of pulmonary sequestration is unknown. Development of ELS from an accessory lung bud, which arises cau- dally from primitive foreg ut, is postulated. It is theorized that this CASE 7 51 Table 7.1 Intralobar sequestration Extralobar sequestration Frequency 75% 25% Appearance Within visceral pleura of the normal lung Enclosed in a separate pleural sac Sex ratio 1M:1F 4M:1F Site 98% lower lobe 60% left-sided 95% left-sided 75% within costophrenic angle 10 \200\22315% sub-diaphragmatic Presentation Rare <2 years, often history of recurrent pneumonia in adulthood 61% at <6 months Asymptomatic cases (incidental finding) 15% 10% segment retains splanchnic (systemic) blood supply generating trac- tion on the lung fragme nt, which subsequently segregates from the main lung mass. The origin of ILS is contentious. The \200\230congenital \200\231 hypothesis mirrors that of ELS formation, whereas in the \200\230acquired \200\231 theory, ILS arises from transfo rmation of chronically inflamed normal lung (pseu- dosequestration), i.e. the presence of a n obstructed bronchus (medi- ated by inflammation, aspiration or infection) causing seconda ry occlusion of the local pulmonary artery supply leading to systemic arterial parasitisati on with vessel incorporation into the, now seques- tered, pulmonary tissue. \227\206 Patients often present with cough +/ \200\223 sputum production, recurrent pneumo nia or features secondary to related anomalies. Superimposed infections, i.e. fungal, tuber culosis, massive haemoptysis, haemothorax and cardiovascular complications can occur. Benig n and malignant tumors have been reported arising in sequestered lung. \227\206 Chest radiography typically shows lower lobe homogeneous consolida- tion or a mass. Cavitation and cystic areas may occur.