Toxins Radiotherapy, high concentration oxygen, paraquat Wegener \200\231s granulomatosis, Churg \200\223Strauss syndrome, Goodpasture \200\231s syn drome, SLE, microscopic polyangiitis, idiopathic haemosiderosis Vasculitis/ alveolar hemorrhage Pulmonary venous hypertension Cardiogenic pulmonary oedema, pulmonary veno-occlusive disease Miscellaneous Sarcoidosis, cryptogenic organizing pneumonia (COP), eosinophilic pneumonia, lipoid pneumon ia Idiopathic interstitial pneumonias Chronic (months \200\223 years) Idiopathic pulmonary \201 brosis (IPF), non-speci \201 c interstitial pneumonia (NSIP), desquamative interstitial pneumonia (DIP), lymphocytic interstitial pneumonia (LIP), respir atory bronchiolitis-associated interstitial lung disease (RB-ILD) Inhalational Inorganic Asbestosis, coal worker s pneumoconiosis, silicosis, metals, e.g. cobalt, aluminum Organic Hypersensitivity pneumonitis, e.g. bird fancier s lung, farmer s lung Connective tissue disease Rheumatoid arthritis, SLE, scleroderma, poly- and dermatomyositis, enclosing spondylitis, S j gren \200\231s syndrome, Beh et \200\231s disease Malignancy Lymphangitis carcinomatosa, bronchoalveolar cell carcinoma, pulmonary lymphoma Miscellaneous Bronchiectasis, Langerhans cell histiocytosis, amyloidosis, lymphangioleiomyomatosis, alveo lar proteinosis, microlithiasis 32 CHAPTER 6 Diffuse lung disease Clinical assessment and imaging History Clinical features may provide useful clues to the u nderlying diag- nosis. Key points in the history are: Presenting symptoms \200 Breathlessness is the most common symptom, and its rate of onset may be useful diagnostical ly (see Table 6.1) Causes of truly episodic breathlessness/diffuse CXR shadowing include eo sinophilic pneumonia, vasculitis, Churg \200\223Strauss syndrome, hypersen- sitivity pneumo nitis, cryptogenic organizing pneumonia, allergic bronchopulmonary aspergillosis, and pulmo nary oedema Cough may occur, although its diagnostic value is uncertain; it may be a promin ent symptom in lymphangitis carcinomatosis, hypersen- sitivity pneumonitis, cryptogenic org anizing pneumonia, sarcoid, and eosinophilic pneumonia. Chronic production of purulent sput um sug- gests bronchiectasis. Bronchorrhoea (production of large volumes of sputum) may occ ur with bronchoalveolar cell carcinoma. Haemoptysis suggests alveolar hemorrhage, malignanc y, or pulmonary venous hypertension Wheeze may occur in asthma associated with eosinophilic pneumonia or Churg \200\223Strauss syndrome Weight loss and fever are non-speci \201 c sy mptoms associated with many diffuse lung diseases. Other medical conditions e.g. malignancy, connective tissue disease, HIV infection, other i mmunosuppression. Ask about old CXRs, which may be helpful in assessing disease duration. Drugs \200 \200 See Table 6.1 for common drug causes of diffuse lung disease Delays of months or even years may occur between starting the drug and developing lung involvement Illicit drug abuse (cr ack cocaine or heroin \200\224pulmonary oedema, eosinophilic pneumonitis, diffuse alveolar hemorrhage, interstitial pneumonia; intravenous drug use \200\224IV talcosis, septic emboli ) Oily nose drops (lipoid pneumonia). Occupation, lifestyle, hobbies, and pets \200 May involve inhalation of inorganic or organic dusts. Document lifelong employment history, including probable exposure levels, use of protective equipment, and names of employers In organic dusts associated with development of diffuse lung disease include asbestos, silica, cobalt, beryllium, aluminum, isocyanates, copper sulfate, iron, tin, barium, and antimony Hypersensitivity pneumonitis may result from inhalation of organic dusts such as Thermoacti nomycetes in moldy hay (farmer s lung), avian proteins or feathers (bird fancier s lung), m ushroom compost, moldy cheese, cork or sugar cane, and isocyanates Risk factors for immunoc ompromise (opportunistic infection, LIP, lymphoma) CLINICAL ASSESSMENT AND IMAGING 33 Smoking history (Langerhans cell histiocytosis, respiratory bronchiolitis- associated inter stitial lung disease, desquamative interstitial pneumonia, and Goodpasture \200\231s syndro me are more common in smokers). Evidence of extrapulmonary disease Manifestations of connective tissue disease, vasculitis, sarcoidosis, e.g. arthralgia, skin rash, ocular symptoms, muscular pain and weakness, Rayn aud \200\231s, nasal/sinus disease, haematuria. Infertility in males (immotile cilia syndro me, cystic \201 brosis). Travel Tuberculosis, pulmonary eosinophilia from parasites (tropics), his- toplasmosis (nor th and central United States, parts of South America and Africa), hydatid disease (Middle E ast, Australasia, Mediterranean). Family history A1-antitrypsin de \201 ciency, rare famil ial forms of UIP and sar- coidosis. Examination \200 \200 \200 Cyanosis and signs of cor pulmonale in severe disease Clubbing (usual interstitial pneumoni tis, asbestosis, bronchiectasis) Basal crackles (usual interstitial pneumonitis, asbestosis , connective tissue disease, pulmonary oedema, lymphangitis, drugs); crackles in bronchiect asis are characteristically coarse Absence of crackles despite a signi \201 cant CXR abnor mality may be suggestive of sarcoidosis, pneumoconiosis, hypersensitivity pneumonitis, or L angerhans cell histiocytosis Squeaks suggest the presence of bronchiolitis Skin, joint, and eye disease (connective tissue disease, sarcoidosis, vasculitis). \200 Imaging CXR is an essential test and is diagnostic in at least 50% of cases. Up to 10% of p atients with biopsy-proven diffuse lung disease have a normal CXR, however. Previous CXRs a re helpful in assessing disease duration and progression. High-resolution CT (HRCT) chest is more sensitive and speci \201 c than CXR for diagnosing diffuse lung disease (see following page and Appendix 4). HRCT is often in itself diagnost ic and should always precede biopsy in the investigation of diffuse lung disease. HRCT also enables assessment of disease extent, and optimal biopsy site if required. HRCT appearance correlates to some extent with disease activity in the interstitial pneu- monias: a predom inantly \200\230ground-glass \200\231 appearance may signify a steroid- responsive in \202 ammatory state, whereas reticulation and honeycombing are often associated with \201 brosis, poor response to treatment, and a worse prognosis. 34 CHAPTER 6 Diffuse lung disease HRCT diagnosis HRCT (and to a limited extent CXR) appearances can be classi \201 ed accord ing to the pattern and distribution of disease, and the presence of additional features (se e also Appendix 4). 1. Imaging pattern Reticular (or linear) pattern Causes include: \200 \200 Interstitial pulmonary oedema Usual interstitial pneumonitis (UIP; reticular shadowing is t ypically patchy, subpleural, and basal; other features include loss of architecture of seco ndary pulmonary lobules, honeycombing, ground-glass change, traction bronchiectasis) Asbest osis (similar features to UIP, often with pleural plaques) Connective tissue disease associ ated \201 brosis (similar features to UIP) Chronic hypersensitivity pneumonitis (often as sociated with regions of ground-glass change, air-trapping on expiration, and centrilobular micronodules) Drug-induced \201 brosis Sarcoidosis. \200 \200 \200 Nodular pattern consists of numerous discrete, round opacities 0.1 \200\2231 cm in diameter . \200 Interstitial processes result in nodularity within interlobular septa, around bronchovascul ar bundles, and subpleurally (e.g. sarcoidosis, which may demonstrate associated perihilar reticular shadowing and lymphadenopathy) Airspace diseases may lead to affected acini becom ing visible as nodules (e.g. hypersensitivity pneumonitis, miliary TB, COP, malignancy). Ground-glass change is an increase in lung density through which pulmo- nary vasculature is still visible (compare the lung density with that of air within the bronchi). May occur as a result of airspace or interstitial disease, and may be patchy or diffuse. Causes include : \200 Pulmonary oedema or hemorrhage, ARDS \200 Hypersensitivity pneumonitis \200 Dr ugs \200 Certain idiopathic interstitial pneumonias (NSIP, RB-ILD, DIP, AIP) \200 PCP \200 Sarcoidosis \200 Bronchoalveolar cell carcinoma \200 Alveolar proteinosis. Ground-glass appearance may be artefactual, the increased density resulting from breath-hol ding during expiration. It may also be confused with \200\230mosaic perfusion \200\231, wh ere densities vary in different regions of the lung as a result of variable perfusion, e.g. in chronic thromboembolic disease, small airways disease. Consolidation (or airspace shadowing) is an increase in attenuation characterized by air br onchograms (air- \201 lled bronchi superimposed against opaci \201 ed alveoli) and the lo ss of visibility of adjacent vessels. It occurs as HRCT DIAGNOSIS 35 disease processes in \201 ltrate and \201 ll alveolar airspaces, for example, with water , blood, pus, malignant cells, or \201 brous tissue. Causes include: \200 \200 \200 \200 \200 \200 Pneumonia Pulmonary oedema or hemorrhage, ARDS Drugs Cryptogenic organizing pneumonia (COP) Bronchoalveolar cell carcinoma, lymphoma Other rare conditions (e.g. eosinophilic pneumoni a, alveolar proteinosis). Cystic change refers to well-de \201 ned air spaces with a thin wall. Causes include: \200 Langerhans cell histiocytosis (bizarrely shaped cysts and nodules, apical predominance) Usu al interstitial pneumonitis (subpleural honeycombing) PCP Lymphocytic interstitial pneumoni a Septic emboli Lymphangioleiomyomatosis (thin-walled cysts, otherwise normal lung) Centril obular emphysema may simulate cystic disease, but there is absence of a well-de \201 ned w all. \200 \200 \200 \200 \200 Interlobular septal thickening occurs as a result of processes affecting the lymphatics or venules within interlobular septa, such as: \200 \200 Pulmonary oedema (smooth thickening) Lymphangitis carcinomatosis (irregular, nodular thicke ning of interlobular septa and bronchovascular bundles, no architectural distortion) Sarcoi dosis Usual interstitial pneumonitis. \200 2. Imaging distribution \200 Upper zone: silicosis, pneumoconiosis, chronic sarcoidosis, hypersensi- tivity pneumonitis, ankylosing spondylitis, tuberculosis, Langerhans cell histiocytosis Lower zone: UIP, conne ctive tissue diseases, asbestosis Mid-zone: sarcoidosis, pulmonary oedema, Pneumocystis car inii pneumonia Peripheral: UIP, eosinophilic pneumonia, drugs (amiodarone), COP Sharp borde rs: radiation pneumonitis. \200 \200 Additional imaging features \200 Lymphadenopathy: sarcoidosis, lymphoma, malignancy, infection, silicosis, berylliosis, LIP Pleural effusion/involvement: pulmonary oedema, connective tissue diseases, infection, mali gnancy, asbestosis, drugs, LAM. Further information Ryu JH et al. Diagnostic approach to the patient with diffuse lung dise ase. Mayo Clin Proc 2002; 77: 1221 \200\2237 36 CHAPTER 6 Diffuse lung disease Further investigations Urine and blood tests Consider the following investigations: \200 Urine dipstick and microscopy for detection of renal disease associated with vasculitis/con nective tissue disease ESR, CRP, FBC (look speci \201 cally at the eosinophil count), rena l and liver function, calcium (increased in >10% of patients with sarcoidosis) Autoantibodi es (including anti-Jo-1, occurs with myositis-associated interstitial pneumonia; positive r heumatoid factor or ANA may occur in infection, malignancy, and UIP as well as in connectiv e tissue disease) ANCA (vasculitis), anti-GBM (Goodpasture \200\231s syndrome) Serum precip itins (to antigens in hypersensitivity pneumonitis; poor speci \201 city) Serum ACE levels may be increased in sarcoidosis, but this is a non- speci \201 c and relatively insensiti ve test and is unhelpful diagnostically. \200 Sputum \200 \200 Cytology may be diagnostic in bronchoalveolar cell carcinoma Induced sputum may be useful i n the diagnosis of PCP and TB. Pulmonary function tests \200 Useful in assessing severity of disease and response to treatment, but often unhelpful diag nostically Typically show restrictive pattern with reduced vital capacity and transfer fact or. Normal values do not exclude mild, early lung disease Obstructive pattern rare, but may be seen in sarcoidosis, Langerhans cell histiocytosis, and lymphangioleiomyomatosis; may s ee mixed picture if coexisting COPD Transfer factor may be increased transiently (days) in alveolar hemorrhage. Reduced transfer factor with preserved lung volumes in scleroderma is suggestive of pulmonary vascular disease (such as pulmonary arterial hypertension or vascul itis) Disease progression and response to treatment are best assessed by serial measurement s of vital capacity and transfer factor Check oxygen saturation and consider ABGs. A fall i n oxygen saturation on simple exercise may be performed in the clinic setting, and is a use ful clue to underlying lung disease in patients with normal saturation and lung function at rest and an unremarkable CXR. Cardiac investigations \200 ECG Conduction abnormality in sarcoidosis; cardiogenic pulmonary oedema is unusual in the p resence of a completely normal ECG Echocardiography Assess left ventricular and valvular fu nction if cardiac pulmonary oedema suspected, and measure pulmonary arterial pressure in sc leroderma and suspected pulmonary veno-occlusive disease. Bronchoalveolar lavage \200 Most useful in diagnosis of opportunistic infection (bacterial or fungal pneumonia, tubercu losis, PCP), malignancy, alveolar proteinosis, eosinophilic pneumonia, and alveolar hemorrh age BAL differential cell counts usually unhelpful diagnostically. FURTHER INVESTIGATIONS 37 Lung biopsy Which patients need a lung biopsy? In cases of uncertain etiology, despite clin ical assessment and HRCT, lung biopsies often provide a de \201 nitive diagnosis. Ideally, they should be taken before treatment is started. The decision to biopsy varies amongst cl inicians, and should take into account the individual patient \200\231s clinical condition and wishes, and the likely bene \201 t of a de \201 nitive diagnosis in terms of predicti ng treatment response and prognosis. Some take a pragmatic approach when a diagnosis (or gr oup of diagnoses with the same treatment) is likely, but not biopsy-proven, and treat empir ically. In some cases, the patient may be too unwell for biopsy and require empirical treat ment. Biopsy of end- stage \201 brosis is unhelpful in eliciting an underlying etiology. Biopsy techniques Transbronchial biopsy provides small samples, but relatively high diag- n ostic yield in diseases with a \200\230centrilobular \200\231 distribution, e.g. sarcoidos is, hypersensitivity pneumonitis, malignancy, infection (fungi, tuberculosis), and cryptoge nic organizing pneumonia. Take 4 \200\2236 samples. Additional blind endobronchial biopsies may be diagnostic in sarcoidosis. Open lung biopsy via thoracotomy or video-assisted thora coscopic (VATS) biopsy provide larger samples than TBB and have diagnostic yields of at lea st 90%. Both require general anesthesia. VATS probably has a lower morbidity and is general ly preferred in stable patients; open biopsy is required in ventilator-dependent patients. Open or VATS biopsy (rather than TBB) is required for diagnosis of idiopathic interstitial pneumonias, vasculitis, lymphoma, lymphangio- leiomyomatosis, and Langerhans cell histiocyt osis. Percutaneous image-guided biopsy may be useful in the diagnosis of well- localized an d dense peripheral in \201 ltrates. A cutting needle biopsy tech- nique is best and, if th e lesion(s) abuts the pleural surface, pneumothorax is uncommon. This page intentionally left blank 39 Chapter 7 Haemoptysis Clinical assessment and causes 40 Investigations 42 40 CHAPTER 7 Haemoptysis Clinical assessment and causes Haemoptysis is a common and non-speci \201 c feature, and c an be a sign of signi \201 cant underlying lung disease. In up to one-third of cases, no c ause is found. An early assessment of the likely underlying cause needs to be made and inve stigated accordingly. Diagnostic approach to haemoptysis Small volume haemoptysis is a comm only encountered problem in the out-patient department. It can be safely and ef \201 cient ly investigated as an out-patient. Massive haemop- tysis is usually encountered in the acci dent and emergency department or in a patient already on the ward with known underlying lun g disease. The approaches to small volume and massive haemoptysis are different. History \200 \200 \200 \200 Past history of lung disease? Document volume of blood and whether old (altered) or fresh T ime course (intermittent, constant) De \201 nitely from the airway, and not from the nose or mouth, or haematemesis? (haemoptysis may be swallowed and then vomited) Presence of syst emic features \200\224associated infection, symptoms consis- tent with underlying malignanc y or vasculitis? Examination May be normal or show signs of underlying lung disease, e.g. bronchiectasis, br onchial carcinoma, or symptoms of circulatory collapse. In practice the usual differential diagnosis lies between: \200 \200 \200 \200 Malignancy Bronchiectasis Tuberculosis/infection PE. Causes of haemoptysis Common \200 Bronchial tumor (benign, e.g. carcinoid or malignant). Haemoptysis is a common presenting f eature of bronchogenic malignancy, indicating endobronchial disease, which may be visible e ndoscopically Bronchiectasis. Small volume haemoptysis is a common feature of bronchiectasi s, particularly during exacerbations. It can be a cause of massive haemoptysis from dilated and abnormal bronchial artery branches that form around bronchiectatic cavities Active tub erculosis. Haemoptysis occurs in cavitating and non-cavitating disease, active disease and inactive disease (e.g. from an old bronchiectatic cavity, which might contain a mycetoma) P neumonia (especially pneumococcal disease) Pulmonary thromboembolic disease Vasculitides/al veolar hemorrhage syndromes, e.g. Wegener \200\231s granulomatosis, SLE, Goodpasture \200 \231s syndrome Warfarin with any of the above. \200 \200 CLINICAL ASSESSMENT AND CAUSES 41 Rare \200 \200 \200 \200 \200 Lung abscess Mycetoma Fungal/viral/parasitic infections Fat embolism Arteriovenous malforma tion, e.g. in hereditary haemorrhagic telangiectasia (HHT) (see p 618) Severe pulmonary hyp ertension (see p 385) Mitral stenosis (rare) Congenital heart disease Aortic aneurysm Asper gillus \200\224invasive fungal disease (intracavity mycetoma) can be a cause of massive hae moptysis Coagulopathy, including disseminated intravascular coagulation Endometriosis Pulmo nary haemosiderosis Iatrogenic, e.g. lung biopsy, bronchoscopy. \200 \200 \200 \200 \200 \200 \200 42 CHAPTER 7 Haemoptysis Investigations The investigation of haemoptysis can often be carried out as an out-patient, but patients with signi \201 cant bleeding or a likely serious underlying cause should be admitted if there are concerns. NB. Beware of the apparently small bleed, which is a sentinel/herald bleed for massive bleeding. This is fortunately rare. Out-patient investigations and management First-line investigations \200 Blood tests FBC, clotting, group and save. If systemic vasculitis is suspected, renal funct ion and a urine dip and microscopy for casts are necessary, as well as autoantibodies \200 \224ANCA, anti-GBM, and ANA Sputum cytology and M, C, & S and AFB if infection suspected CX R may show mass lesion, bronchiectasis, consolidation, or an AVM CT chest should be done pr ior to bronchoscopy, as prior knowledge of the site of abnormality leads to increased pick- up rates at bronchos- copy. Similarly, a de \201 nitive diagnosis, e.g. AVM, may be made f rom the CT, obviating the need for further investigations. This depends on local resources CT may miss an upper airway abnormality, but bronchoscopy should not Bronchoscopy to visual ize the airways and localize the site of bleeding. May also be therapeutic, for example if a bleeding tumor can be injected with a vasoconstricting agent (adrenaline) or a catheter i nserted for tamponade (see massive haemoptysis) Transbronchial biopsies \200\224if vasculit is suspected. \200 \200 Second-line investigations Usually done if \201 rst-line investigations fail to demonstra te a cause. \200 \200 CTPA to exclude PE Bronchial angiogram Diagnostic and therapeutic. Rare for the actual blee ding site to be identi \201 ed; more often the bleeding site is assumed from visualizing a mesh of dilated and tortuous vessels, e.g. around a bronchiectatic cavity. Usually done du ring an episode of bleeding to maximize the chance of identifying the site of bleeding Bron chial artery embolization Therapeutic approach to embolize the bleeding artery, usually wit h coils or glue (specialist center only). There is a small risk of paraplegia (<1%) if the anterior spinal artery originates from the bronchial arterial circulation ENT review The so urce of the bleeding may be the upper airway Echocardiogram Moderate/severe PHT can cause h aemoptysis, especially in a patient on anticoagulants. \200 Cryptogenic haemoptysis In around one-third of cases, despite appropriate investigations as above, no cause for the haemoptysis can be found. This has a good prognosis. Often the hae moptysis will settle without treatment and will become less worrying to the patient over ti me, especially as investigations have failed to determine the cause. Massive haemoptysis (1 00 \200\223600 mL blood in 24 h) is a life-threatening emergency, with a mortality of up to 80%. INVESTIGATIONS 43 22 Management of massive haemoptysis Massive haemoptysis (100 \200\223600 mL blood in 24 h) is a life-threatening emergency, with a mortality of up to 80%. It is extremely distressin g for the patient, relatives, and medical staff, but is fortunately rare. Investigations wi ll follow treatment, which may be dif \201 cult, and is often unsuccessful. In some cases, active treatment may be inappropriate, and palliative treatment with oxygen and diamorphin e may be warranted. \200 Protection of the non-bleeding lung is vital to maintain adequat e gas exchange. This may involve lying on the bleeding side (to prevent blood \202 owing into the unaffected lung), or intubation with a double lumen tube. If intubation is not nee ded, or not appropriate, give high \202 ow oxygen. \200 Airway protection and ventilation Cardiovascular support: \200 \200 \200 \200 \200 Nebulized adrenaline (5 \200\223 10 mL of 1 in 10,000) Oral tranexamic acid (500 mg tds, not if in severe renal failure) CXR 9 chest CT (depending on stability of patient) Early bronchoscopy \200\224diagnostic and t herapeutic Rigid bronchoscopy (with general anesthesia) is preferable. May allow localizati on of the site of bleeding; balloon tamponade with a Fogarty catheter Bronchial artery embo lization \200\224therapeutic approach to embolize bleeding artery, usually with coils or gl ue (specialist center only) Surgery \200\224resection of bleeding lobe (if all other measur es have failed). large bore/central intravenous access clotting factors, group and save \202 uid resuscita tion 9 transfusion reverse anticoagulants inotropes \200 \200 \200 \200 This page intentionally left blank 45 Chapter 8 Pleural effusion Clinical assessment 46 Diagnostic algorithm for the patient with a pleural effusion 48 Tran sudative pleural effusions 49 Exudative pleural effusions 50 Pleural \202 uid analysis 1 52 Pleural \202 uid analysis 2 54 46 CHAPTER 8 Pleural effusion Clinical assessment Pleural effusion is a common presentation of a wide range of different diseases. Commonest causes in UK and USA (in order): cardiac failure, pneumonia, malignancy , pulmonary embolism. Priority is to make a diagnosis and relieve symptoms with minimum num ber of invasive procedures. The majority of patients do not require a chest drain and can b e managed as out-patients. Procedures such as therapeutic thoracentesis may be performed re adily on a day unit. Consider admission and chest drain insertion for: \200 \200 Patients with malignant effusions who are candidates for pleurodesis Empyema or parapneumon ic effusion with purulent \202 uid or a pleural \202 uid pH <7.2 (the majority of these effusions are unlikely to resolve without drainage and antibiotics) Patients who are unwel l with an acute massive effusion. Key steps in the management of the patient with a pleural effusion (see also abbreviated al gorithm in following section). 1. History, examination, CXR (PA and lateral). 2. Does the p atient have heart failure? If so, this should be treated, with no need for pleural tap unle ss atypical features (such as very asym- metrical bilateral effusions, unilateral effusion, chest pain, or fever) or fails to respond within 3 days (75% of cardiac failure effusions resolve following 48 h of diuresis). 3. Thoracentesis (= \200\230pleural tap \200\231 or p leural \202 uid aspiration) may be diagnostic and/or therapeutic, depending on the volume of \202 uid removed. See p 782 for procedure details, and pp 52-55 for pleural \202 ui d analysis. Following diagnostic tap: \200 \200 Note pleural \202 uid appearance Send sample in sterile pot to biochemistry for measureme nt of protein and LDH Send a fresh 20-mL sample in sterile pot to cytology for examination for malignant cells and differential cell count Send samples in sterile pot and blood cultu re bottles to microbiology for Gram stain and microscopy, culture, and AFB stain and cultur e Process non-purulent heparinized samples in arterial blood gas analyzer for pH Consider m easurement of cholesterol and triglycerides, haematocrit, glucose, and amylase, depending o n the clinical circumstances. If the patient is breathless they may bene \201 t from removal of a larger volume of \202 uid (therapeutic tap, p 783). 4. Is the pleural effusion a transudate or exudate? Help ful in narrowing the differential diagnosis. In patients with a normal serum protein, pleur al \202 uid protein <30 g/L = transudate and protein >30 g/L = exudate. In borderline cas es (protein 25 \200\22335 g/L), or in patients with CLINICAL ASSESSMENT 47 abnormal serum protein, apply Light \200\231s criteria \200\224effusion is exudative if it meets one of following criteria. \200 \200 Pleural \202 uid protein/serum protein ratio >0.5 Pleural \202 uid LDH/serum LDH ratio >0.6 Pleural \202 uid LDH >two-thirds the upper limit of normal serum LDH. These criteria are very sensitive in the diagnosis of exudative effusions, although may occ asionally falsely identify transudates as being exudates, e.g. patients with partially trea ted heart failure on diuretics may be mis- identi \201 ed as exudates. 5. Further investig ations if the diagnosis remains unclear: \200 CT chest with pleural contrast (ideally scan prior to complete \202 uid drainage, to impr ove images of pleural surfaces; useful in distinguishing benign and malignant pleural disea se, p 346). Repeat pleural \202 uid cytology Further pleural \202 uid analysis (p 54), e.g. cholesterol, triglyceride, haematocrit, glucose, amylase, fungal stains Pleural tissue biopsy for histology and TB culture (ultrasound- or CT-guided, closed Abrams \200\231, or thoracoscopic biopsy; image-guided biopsies are superior to Abrams \200\231 for malignant d isease; use Abrams \200\231 biopsy only in cases when tuberculosis is suspected; thoracosco py is \200\230gold-standard \200\231; biopsies have sensitivity of 90% for malignancy and allow therapeutic talc pleurodesis at the same time) Reconsider pulmonary embolism and tube rculosis Consider thoracoscopy if persistent undiagnosed pleural effusion. \200 \200 Bronchoscopy has no role in investigating undiagnosed effusions unless the patient has haem optysis or a CXR/CT pulmonary abnormality. Pleural \202 uid may compress the airways and limit bronchoscopic views, and so if bronchoscopy is indicated it is best performed followi ng drainage of the effusion. Further information Holm KA, Antony VB. Pleural effusions: the workup and treatment. J Resp ir Dis 2001; 22: 211 \200\22319 Light RW. Pleural effusion. N Engl J Med 2002; 346: 1971 \200\2237 Maskell NA, Butland RJA. BTS Guidelines for the investigation of a unilateral pleural effus ion in adults. Thorax 2003; 58 (suppl. II) ii8 \200\22317 48 CHAPTER 8 Pleural effusion Diagnostic algorithm for the patient with a pleural effusion 1. History, examination, CXR 2 . Does the patient have heart failure with no atypical features (such as asymmetrical bilat eral effusions, unilateral effusion, normal heart size on CXR, chest pain, fever)? No Yes Diuresis Effusions persist 3. Thoracentesis (diagnostic 9 therapeutic). Pleural \202 uid analysis: appear- ance, pro tein, LDH, cytology, microbiology, pH (9 cholesterol, triglyceride, haematocrit, glucose, a mylase). 4. Is the pleural effusion a transudate or exudate? Exudate Transudate Treat cause Effusion persists 5. Further investigations if diagnosis remains unclear: \200 \200 \200 CT chest with contrast to enhance pleura Repeat pleural \202 uid cytology Further pleural \202 uid analysis, e.g. cholesterol, triglyceride, haematocrit, glucose, amylase, fungal stains Pleural tissue biopsy for histology and TB culture (ultrasound- or CT-guided, close d Abrams \200\231, or thoracoscopic biopsy) Reconsider pulmonary embolism and tuberculosis Consider thoracoscopy if persistent undiagnosed pleural effusion. \200 TRANSUDATIVE PLEURAL EFFUSIONS 49 Transudative pleural effusions Mechanisms involve either increased hydrostatic pressure or reduced osmotic pressure (due to hypo-albuminaemia) in the microvascular circulation. Differential diagnosis Table 8.1 Causes of transudative pleural effusions Cause Notes Common Left ventricular failure Investigate further if atypical features (very asymmetrical bilateral effusions, unilateral effusion, chest pain, fever); frequently complicated by pulmonary embolism (up to one- \201 fth of cases at autopsy) Cirrhotic liver disease ( \200\230hepatic hydrothorax \200\231) Ascites often but not invariably present; majority right-sided; remove ascites and treat hy po-albuminaemia (p 244) Pulmonary embolism 10 \200\22320% are transudates (p 401) Peritoneal dialysis Pleural \202 uid analysis resembles dialysis \202 uid, with protein <1 g/dl and glucose >300 mg/dl Nephrotic syndrome Usually bilateral; consider secondary pulmonary embolism if atypical features Atelectasis Common on ITU or post-operatively; usually small effusion, may be bilateral; rarely needs i nvestigation Less common Constrictive percarditis May be unilateral or bilateral Hypothyroidism May be transudate or exudate; pleural effusions occur most commonly in association with asc ites, pericardial effusion, and cardiac failure, although may be an isolated \201 nding Meigs \200\231 syndrome Unilateral (often right-sided) or bilateral pleural effusions and ascites; occurs in women with ovarian or other pelvic tumors; resolves following removal of tumor Urinothorax Effusion ipsilateral to obstructed kidney with retro-peritoneal urine leak, resolves after treatment of obstruction; pleural \202 uid smells of urine, pH usually low; pleural \202 uid creatinine >serum creatinine is diagnostic Malignancy Up to 5% are transudates Treatment of transudative effusions is directed at the underlying cause; consider further i nvestigation if fails to respond. CHAPTER 8 Pleural effusion 50 Exudative pleural effusions Mechanisms involve an increase in capillary permeability and im paired pleural \202 uid resorption. Differential diagnosis Table 8.2 Causes of exudative pleural effusions. Cause Notes Common Parapneumonic effusion Occurs in 40% of bacterial pneumonias; commonest exudative effusion in young patients (p 420) Malignancy Commonest exudative effusion in patients >60 years (p 279) Pulmonary embolism 80 \200\22390% are exudates (p 401) Rheumatoid arthritis Typically low pleural \202 uid glucose, often <1.6 mmol/L (p 188) Mesothelioma Pleural \202 uid cytological analysis has low sensitivity (p 114) Less common Empyema Pleural \202 uid pH <7.2; clinical features of infection, e.g. fever, sweats (p 352) Tuberculosis Typically lymphocytic effusion; pleural \202 uid AFB smear positive in 10% of cases, cult ure positive in 25%, Abrams \200\231 biopsy histology sensitivity 90% (p 490) Other infections Very rare; include viral, parasitic, rickettsial, and fungal (e.g. aspergillus, histoplasma , coccidioidomycosis) Hepatic, splenic, or subphrenic abscess Oesophageal rupture Initially sterile exudate, followed by empyema; pH <7.2, raised salivary amylase, often his tory of vomiting Pancreatitis Pleural \202 uid pancreatic amylase may be raised SLE Lupus erythematosus cells in \202 uid are diagnostic; may respond quickly to prednisolone Other autoimmune diseases Churg \200\223Strauss syndrome (intensely eosinophilic \202 uid), Sj gren \200\231s synd rome, scleroderma, dermatomyositis, Wegener \200\231s granulomatosis Sarcoidosis Effusions are uncommon Pleural effusions common; may be blood-stained Post-cardiac injury syndrome (Dressler \200\231s syndrome) Post-coronary artery bypass surgery (p 361) EXUDATIVE PLEURAL EFFUSIONS 51 Table 8.2 Causes of exdative pleural effusions (cont.) Cause Notes Less common Radiotherapy May cause small, unilateral effusions up to 6 months after treatment Uraemia Effusions frequently resolve after starting dialysis Chylothorax Presence of chylomicrons or pleural \202 uid triglyceride level >110 mg/dl (p 55) Benign asbestos-related pleural effusion (p 110) Drug-induced Drugs include amiodarone, bromocriptine, methotrexate, phenytoin, and nitrofurantoin; see w ww. pneumotox.com for full list; effusions usually resolve following discontinuation of dru g Other, rare causes Include yellow nail syndrome, cryptogenic organizing pneumonia, amyloidosis, familial Medit erranean fever Treatment of exudates involves treatment of the underlying cause, as well as measures to im prove breathlessness and remove pleural \202 uid, e.g. therapeutic thoracentesis (p 783), intercostal drainage (p 760), and pleurodesis (p 776). 52 CHAPTER 8 Pleural effusion Pleural \202 uid analysis 1 \200\230Routine \200\231 pleural \202 uid analysis compris es assessment of: \200 \200 \200 Pleural \202 uid appearance Biochemistry (protein and LDH) Cytology (for malignant cells and differential cell count; ideally fresh 20-mL sample) Microbiology (Gram stain and micro scopy, culture, and AFB stain and culture; inoculation of blood culture bottles with pleura l \202 uid may increase yield) pH Although considered routine, some of these investigations may be unnecessary and even misle ading, depending on the clinical picture (e.g. microbiological analysis on patients suspect ed as having transudates). Additional pleural \202 uid investigations such as measurement of cholesterol and triglyc erides, haematocrit, glucose, and amylase may be helpful in certain clinical circumstances. PLEURAL FLUID ANALYSIS 1 53 Appearance Appearance Possible causes Bloody Trauma, malignancy, pulmonary infarction, pneumonia, post-cardiac injury syndrome, pneumoth orax, benign asbestos-related pleural effusion, aortic dissection/ rupture; de \201 ned as haemothorax if pleural \202 uid haematocrit >50% of peripheral blood haematocrit (p 360) Turbid or milky Empyema, chylothorax, pseudochylothorax (clear supernatant after centrifuging favors empyem a; cloudy after centrifuging suggests chylothorax or pseudochylothorax, p 55) Putrid odor Anaerobic empyema Viscous Mesothelioma Food particles Oesophageal rupture Urine odor Urinothorax Black Aspergillus infection Brown, \200\230anchovy sauce \200\231 Amoebic liver abscess draining into pleural space Differential cell count Predominant cell type Possible causes Neutrophils Any acute effusion, e.g. parapneumonic, pulmonary embolus Mononuclear cells Any chronic effusion, e.g. malignancy, tuberculosis Lymphocytes Tuberculosis, especially if over 80%; other causes include malignancy, sarcoidosis, lymphom a, rheumatoid pleurisy, post-CABG Eosinophils Often unhelpful; associations include air or blood in pleural space (haemothorax, pulmonary infarct, pneumothorax, previous tap), malignancy, infection (parapneumonic, tuberculous, f ungal, parasitic), drug- and asbestos-induced effusions, Churg \200\223Strauss syndrome or idiopathic Mesothelial cells Predominate in transudates; variable numbers in exudates, typically suppressed in in \202 ammatory conditions, e.g. tuberculosis Lupus erythematosus cells Diagnostic of systemic lupus erythematosus 54 CHAPTER 8 Pleural effusion Pleural \202 uid analysis 2 Pleural \202 uid pH and glucose Pleural \202 uid pH may b e measured using an arterial blood pH analyzer. The sample should be appropriately heparini zed, e.g. aspirate a few mL of pleural \202 uid into a pre-heparinized blood gas syringe. Frankly purulent samples should not be analyzed \200\224it is unnecessary, and might damag e the machine. Normal pleural \202 uid pH is about 7.6. An abnormally low pH (<7.3) suggests pleural in \202 ammation and is often associated with a low pleural \202 uid glucose (<3.3 mmol/L o r pleural \202 uid/serum glucose ratio <0.5). The mechanism probably involves increased n eutrophil phagocytosis, and bac- terial or tumor cell breakdown, resulting in the accumulat ion of lactate and carbon dioxide. Causes of low pH and low glucose effusions \200 Parapneumonic effusion and empyema (pH <7.2 indication for drainage of pleural space, as un likely to resolve spontaneously) Rheumatoid pleuritis (glucose <1.7 mmol/L in 66% and <2.8 mmol/L in 80% of cases) Malignant pleural effusion (associated with advanced disease and po or survival, higher sensitivity of pleural \202 uid cytological analysis, and failure of pleurodesis) Tuberculous pleural effusion Oesophageal rupture Lupus pleuritis. \200 \200 Urinothorax is the only transudative effusion that can cause a pH <7.3. An abnormally high (alkaline) pH may rarely occur in the setting of Proteus pleural infection. Pleural \202 uid triglyceride and cholesterol Measure in turbid or milky effusions or where chylothorax is suspected. Chylothorax occurs following disruption of the thoracic duct, and pleural \202 uid may ap pear turbid, milky, serous, or blood-stained. The presence of pleural \202 uid chylomicro ns or a pleural \202 uid triglyceride level >110 mg/dl con \201 rms the diagnosis. Cause s of chylothorax: \200 \200 \200 \200 Malignancy (particularly lymphoma) Trauma Following thoracotomy Pulmonary lymphangioleiomyo matosis. Pseudochylothorax occurs due to cholesterol crystal deposition in chronic effusions, most c ommonly due to rheumatoid pleurisy or tuberculosis, and may cause a milky effusion; raised pleural \202 uid cholesterol (>200 mg/dl) and cholesterol crystals at microscopy distingu ish it from chylothorax. PLEURAL FLUID ANALYSIS 2 55 Pleural \202 uid amylase Abnormal if pleural \202 uid amylase > upper normal limit for serum amylase, or if amylase pleural \202 uid/serum ratio >1.0. Causes include: \200 