Diagnosis Pleural \202 uid analysis Pleural \202 uid characteristics in MPE are: \200 \200 \200 \200 \200 \200 \200 Once malignant cells nest on pleural surfaces, the main mechanism of pleural fluid accumula tion is increased vascular permeability, probably in combination with the obstruction of ly mphatic vessels by the parietal pleural metastases. Patients with cancer may also develop e ffusions from causes unrelated to direct pleural involvement by tumor ( \200\230paramaligna nt \200\231 effusions) such as: \200 \200 \200 Exudate according to Light \200\231s criteria in 98%. Bloody appearance (>10.000 RBC/mm3) i n >40%. Lymphocytes predominance in 80%. Reduced glucose levels (<3.3 mmol/L) in 10 \200 \22330%. Low pH (<7.3) in 20 \200\22335%. Adenosine deaminase (ADA) levels <40 U/L in 95%. Positive panel of tumor markers (CEA>50 ng/mL or CA15.3>75 U/mL or CA125>2800 U/mL or CYFRA 21 \200\2231>175 ng/mL) in about half the cases. Notably, one- third of cytology-negative MPE can be identi \201 ed by at least one of these markers. Positive cytological examinati on in 50% after a single tap attempt; a repeat aspiration is helpful in an additional 10% o f cases. This is the most common way of diagnosing MPE. Post-obstructive pneumonia or atelectasis. Pulmonary embolism. Lymphatic mediastinal blocka de or thoracic duct obstruction (chylothorax). SVCO. Malignant pericardial effusion and car diac tamponade. Post-radio- or chemotherapy. Hypoalbuminemia. \200 \200 \200 Cytological yield depends on: \200 \200 Number of submitted specimens. Type of tumor (e.g. lower positive results with squa- mous c ell carcinomas, mesotheliomas and sarcomas). Tumor burden in the pleural space. Expertise o f the cytophatologist. Clinical features \200 \200 \200 \200 Dyspnoea (the most common symptom). Constitutional symptoms. Cough. Chest pain (particularl y in mesothelioma). \200 In contrast, the volume of pleural \202 uid analyzed does not impact the yield of cytolog ic diagnosis (submission of 5 \200\22310 ml may suf \201 ce). Mean age of patients with MPE is 65 years. AUTHOR \200\231S TIP A pleural effusion in a woman with breast cancer is malignant until pr oven otherwise. AUTHOR \200\231S TIP Pleural \202 uid \202 ow cytometry should be ordered when lymphoma is a consideration. Imaging Chest radiographs (see also Chapter 3.8) Typical radiological appearance of MPE: \200 Closed (blind) pleural biopsy \200 45% sensitivity for MPE. \200 Establish the diagnosi s of malignancy only in 15% of patients with false-negative cytology. Large unilateral pleural effusion (60%). Malignancy is the most common cause of massive ple ural effusions. CHAPTER 14.6 Malignant effusions 343 The most widely used sclerosants are: \200 CT-guided biopsy of the pleura \200 Talc, which is the most effective agent (>90% success rate). Dose: 4g. Doxycycline (effecti veness of 75%). Dose: 0.5g. High diagnostic yield (85%) in the presence of pleural thickening or nodularity. Consider a lso if only a small effusion is present and pleu- ral \202 uid cytology is negative. Pleurodesis can be performed: \200 Insuf \202 ating dry powder talc (poudrage) through a thora- coscope. Instilling, at the b edside, doxycycline or talc (slurry) mixed with saline via a chest tube. Medical thoracoscopy \200 \200 >95% sensitivity for MPE. The recommended procedure when the cytological analysis is negati ve and a substantial amount of pleural \202 uid exists in patients who are \201 t enoug h. The choice of the pleurodesis procedure will depend upon: \200 Thoracoscopy allows: \200 The patient \200\231s characteristics (e.g. bedside pleurodesis would be preferred in those with poor performance sta- tus or contralateral pleuro-pulmonary involvement). The availab ility of an expert thoracoscopist. Biopsies from the chest wall, diaphragm, lung and mediastinum. Staging in lung cancer and m esothelioma. Removal of all pleural fluid and talc pleurodesis if macroscopic tumor is obvi ous. \200 Pleurodesis with doxycycline Insert a small-bore catheter (10 \200\22314F). \200 \200 Prognosis \200 Drain in a controlled fashion. Confirm full lung re-expansion with a chest radiograph. Inje ct 500 mg of doxycycline in 100ml of saline into the pleural space. Clamp chest tube for 1 \200\2232 hours, and then open it for drainage. Remove chest tube within 12 \200\22324 hour s, in the absence of excessive \202 uid drainage (>250 ml/day); otherwise, a second dose of the sclerosing agent can be adminis- tered. The entire pleurodesis procedure can be acco mplished within <24 to 72 hours. Median survival depends upon the site of the primary tumor (5 months, with the shortest in lung and the longest in breast primaries and mesothelioma). A pleural \202 uid pH <7.3 is associated with far advanced disease of the pleural space and a decreased response to pleu rodesis. Treatment Systemic therapy \200 May control effusions in chemo- radio- or hormone-ther- apy responsive tumors, such as lymp homa, SCLC and breast cancer. Some experts favor early pleurodesis in chemo-sensitive tumor s. At least, proceed to aspirate symptomatic pleural effusions before chemotherapy. AUTHOR \200\231S TIP A trial of intrapleural \201 binolytics may be a useful adjunct ther apy for patients with multiloculated MPE who fail to drain adequately, before attempting pl eurodesis. Observation \200 Indicated in asymptomatic patients or when there is no recurrence of symptoms after an init ial therapeutic tho- racentesis (uncommon). Complications of pleurodesis: \200 \200 Therapeutic thoracentesis \200 Pleuritic chest pain and fever (10 \200\22330%). Rarely, acute respiratory failure (ARDS) f ollowing talc administration. Where grade large-particle talc (most particles <10 m remov ed) is used, this com- plication has not been reported. Consider the possibility of an unre cognized air leak if ARDS develops post pleurodesis. Recommended for the palliation of dyspnoea in patients with a very short live expectancy (K arnofsky perform- ance scale score \211 40). Caution should be taken if removing more than 1.5 \200\2232 litres on a single occasion. AUTHOR \200\231S TIP Dyspnoea that does not improve after pleural aspiration suggests pulmo nary carcinomatous lymphangitis, atel- ectasis, pulmonary or tumor embolism, or COPD. Indwelling pleural catheters \200 A chronic indwelling 15.5F pleural catheter is the treat- ment of choice in patients with t rapped lung and is also an effective option if pleurodesis fails. Indwelling pleural cathet er allows patients to drain pleural \202 uid regularly or on an \200\230as required \200 \231 basis at home. A spontaneous pleurodesis will occur in almost 45% of patients. The cat heter remains in place for a median of 2 months, until death or removal. The expensive drai nage supplies (suction bottles) counterbalance hospital cost-savings. Pleurodesis through t he indwelling pleural catheter needs to be explored in future. Pleurodesis With pleurodesis, a chemical irritant is injected into the pleural space, creat ing an intense pleural in \202 ammation, which ultimately leads to the fusion of the visce ral and parietal pleura. Prerequisites for pleurodesis: \200 \200 \200 Symptomatic (dyspnoea) MPE. Reasonable survival expectancy (>1 month). Absence of trapped l ung (de \201 ned as lung failure to re-expand after drainage of an effusion because of mec hanical restriction of the visceral pleura) or main- stem bronchial obstruction. J PORCEL AND F RODRIGUEZ-PANADERO 344 Further reading Janssen JP, Collier G, Astoul P, et al. Safety of pleurodesis with talc pou drage in malignant pleural effusions: a prospective cohort study. Lancet 2007; 369: 1535 \200\2231539. Other options \200 Reserve pleuroperitoneal shunting or surgery (pleurec- tomy or decortication) for selected patients with trapped lung or failed pleurodesis. In patients with chy- lothorax, pleuroper itoneal shunt may preserve nutri- tional status. Bronchoscopic removal of tumor masses in t he large airways provoking atelectasis may allow subsequent pleurodesis. Light RW. Pleural Diseases 5th edn. Philadelphia: Lippincott Williams & Wilkins, 2007. Light RW, Gary Lee YC. Textbook of Pleural Diseases, 2nd edn. London: Hodder Arnold, 2008. Rodriguez-Panadero F, Janssen JP, Astoul P. Thoracoscopy: general overview and place in the diagnosis and management of pleural effusion. Eur Respir J 2006; 28: 409 \200\223421. Key points \200 Stather DR, Tremblay A. Use of tunneled pleural catheters for out- patient treatment of mal ignant pleural effusions. Curr Opin Pulm Med 2007; 13:328 \200\22333. Consider the diagnosis of MPE in patients with: \200 \200 \200 Thoracoscopic insuf \202 ation of talc may be the optimal technique for pleurodesis in patients with MPE. If th oracoscopy is not available or the patient is too frail, bedside pleurodesis with doxycycli ne or talc slurry is a reliable alternative. Consider indwelling pleural catheter in patien ts with trapped lung or failed pleurodesis. A unilaterally large effusion. A known malignancy. A lymphocytic exudate with normal ADA le vels. Talc poudrage if diagnosis made at thoracoscopy Proven malignant effusion No Is the patient symptomatic? Observe Yes Yes Karnofsky <40? Therapeutic thoracentesis No Talc poudrage if thoracoscopic facilities Chest tube and drainage Consider: 1.Therapeutic bronchoscopy (if bronchial obstruction) 2.Indwelling pleural cathet er 3.Pleuroperitoneal shunt CXR lung expands fully? No Yes Bedside pleurodesis Consider: 1.Repeat pleurodesis 2.Indwelling pleural catheter 3.Serial thoracentesis 4.Pleur operitoneal shunt Yes Recurrence of effusion? Fig. 14.6.1 Algorithm for treating MPE. This page intentionally left blank H DAVIES & G LEE 346 14.7 Malignant mesothelioma De \201 nition Malignant mesothelioma is an aggressive, universally fatal, neoplasm arisin g from the serosal surfaces usually of the pleura (>90%), peritoneum (7%) or rarely the per icardium or tunica vaginalis. Up to 20% of patients may not have identi \201 able predispos- ing factors. Pathogenesis Inhaled asbestos \201 bres can provoke damage (and subse- quent carcinogenes is) in pleural mesothelial cells directly, following translocation of \201 bres from the lung to the pleu- ral surface, or indirectly, through stimulation of oncogenic mediators. T he risk of mesothelioma is related to the biopersistence of the \201 bres in the lung. Lo ng, slender amphibole \201 bres are more dif \201 cult to eliminate than serpentine \201 bres, thus accounting for their signi \201 cantly higher tumorigenic capacity. Incidence There is a global epidemic of mesothelioma. On average one patient dies of mesoth elioma every 4 hours in the UK and the incidence is expected to rise until 2015 (Fig. 14.7. 1). In Western Europe over 250,000 deaths from mesotheli- oma are predicted in the next 20 \200\22330 years. This re \202 ects the latency period (typically 20 \200\22350 years) bet ween prior asbestos exposure and disease onset as use of asbestos was banned in the UK as l ate as 1999. In the USA, an early ban of asbestos use means the incidence of mesothelioma h as peaked, but the disease still kills about 3000 each year. Substantial future increases i n cases are predicted in devel- oping countries where asbestos use remains largely unregula ted. Fig. 14.7.1 shows the number of mesothelioma deaths amongst males in Great Britain sin ce 1968 (dots), the inferred past collective dose of asbestos (exposure index) and an estim ation of projected male mesothelioma cases to 2050. www.hse.gov.uk/statistics/causdis/proj6 801.pdf Clinical features The majority of patients are males (re \202 ecting occupational exposure ) in their \201 fth to seventh decades. Symptoms may include: \200 \200 \200 Dyspnoea, particularly exertional. Chest pain. Constitutional features such as weight loss, sweating and fatigue. Ascites is common with primary peritoneal mesotheli- oma or with per itoneal metastases from pleural mes- othelioma. Symptoms reflecting involvement of adjacent intra- thoracic structures, e.g. esophagus, spinal cord, superior vena cava. Causes Occupational, and occasionally environmental, exposure to asbestos is the commonest cause. Industries associated with signi \201 cant asbestos use include shipbuilding, const ruc- tion and building trades, automotive brake repair and the manufacture of asbestos text iles. There is no safe threshold of exposure to asbestos although the risk of mesothelioma increases with intensity of exposure and duration since \201 rst exposure. Amphibole asbe stos \201 bres (e.g. crocidolite (blue asbestos), amosite (brown asbestos)) are more carc inogenic than serpentine (chrysotile) \201 bres (white asbestos). Other aetiological fact ors include erionite (a non-asbestos \201 bre found in Turkey), exposure to ionizing radi ation, espe- cially thorium dioxide \200\223 a radiographic contrast agent used in the 195 0s. The role of simian virus 40 (SV40) has been implied, but remains unproven, in the patho genesis of mesothelioma. Paraneoplastic syndromes and distant metastases are uncommon. Examination commonly reveals a unilateral pleural effu- sion. Clubbing, if present, often re \202 ects concomitant asbe s- tosis. Subcutaneous masses can occur at the sites of previ- ous pleural intervention, re \202 ecting pleural tract spread. Diagnosis Over 95% of patients with mesothelioma develop a pleural effusion and mesotheliom a should be considered in all patients with a unilateral exudative pleural effusion or pleu ral thickening. There are no speci \201 c radiological fea- tures or blood pro \201 les t hat allow diagnosis of malignant pleural mesothelioma. 2000 200000 Crocidolite Amosite Chrysolite Exposure Index Central estimate Observed Mesothelioma deaths 1800 180000 1600 160000 s t r o p m 1400 140000 s h t a e d I 1200 120000 / e r u s o p x E f x e d n o r e b m u N 100000 1000 800 i 80000 s o t s e b s A 600 60000 400 40000 20000 200 0 0 1900 1905 1910 1915 1920 1925 1930 1935 1940 1945 1950 1955 1960 1965 1970 1975 1980 1985 1990 1995 2000 2005 2010 2015 2020 2025 2030 2035 2040 2045 2050 Year Fig. 14.7.1 Mesothelioma observed and \201 tted/projected deaths among males aged 20 \200 \22389, asbestos imports and estimated/projected exposure inde. CHAPTER 14.7 Malignant mesothelioma 347 De \201 nitive diagnosis can only be made with cytological or histological con \201 rmati on. Histological subtypes Common histological subtypes include: \200 \200 \200 Epithelioid (50 \200\22360%). Sarcomatoid (10%). Mixed (biphasic), a mixture of epithelioid and sarcoma- toid components. These histological subtypes have different gene expression pro \201 les. Differentiating b etween subtypes is important as they vary in their biological behavior and prognostic impli cations. Staging There is no universally accepted staging regimen. Staging is more important in rese arch studies than for clinical use. The Butchart classi \201 cation and the more recent In ternational Mesothelioma Interest Group (IMIG) staging system (based on the tumor-nodal-met astasis (TNM) classi \201 cation) are frequently employed in mesothelioma research trials. Fig. 14.7.2 CT scan revealing a shrunken left hemithorax with circumferential nodular pleur al thickening in a patient with advanced mesothelioma. Imaging guided biopsies are preferred to blind (e.g. Abrams \200\231) biopsies (diagnostic sensitivity 87% v 47% respec- tively) if pleural abnormality is detected. Thoracoscopy allo ws simultanous therapeutic fluid drainage with pleurodesis and diagnostic pleural biopsy (s ensitivity 98%)(Fig. 14.7.3). Investigations Imaging Chest radiography May demonstrate: \200 \200 \200 \200 Unilateral pleural effusion mediastinal shift. Pleural mass (may be multiple). Pleural t hickening: focal or diffuse (lung encasement). Evidence of previous asbestos exposure: pleu ral plaques or interstitial \201 brosis. Local rib invasion. CT with pleural-phase contrast enhancement The following features suggest malignant pleural disease but cannot distinguish pleural mesothelioma from meta- static carcinomas (Fig. 14. 7.2): \200 \200 \200 Pleural effusion with pleural nodularity and enhancement. Mediastinal pleural thickening. L ocal invasion e.g. chest wall and diaphragm. Fig. 14.7.3 Thoracoscopic view of pleural mesothelioma on the parietal pleural surface. Concomitant features of asbestos exposure e.g. pleural plaques or asbestosis may be present . MRI MRI is useful in selected cases to aid de \201 nition of localized disease e.g. ches t wall or spinal cord invasion. PET The clinical role of PET is unclear as it cannot determ ine malignant pleural disease from in \202 ammatory pleuritis. High pleural standard uptak e values (SUV) are associated with a worse prognosis in mesothelioma. Biomarkers No speci \201 c pleural \202 uid or serum marker exists to reliably identify mesothelioma. Pleural \202 uid and blood levels of soluble mesothelin-related protein (SM RP) are signi \201 cantly elevated in patients with mesothelioma, particularly epithelioid subtype, but can also be raised in other tumors (e.g. pancreatic and ovar- ian carcinomas) . The exact role of serum or pleural \202 uid levels of mesothe- lin and other potential markers, such as osteopontin and RCAS1 (a type II membrane protein), in malignant mesotheli oma is the subject of ongoing evaluation. Pleural \202 uid analysis Pleural \202 uid is typically an exudate. Sensitivity of cyto logy is low (usually 20-30%) as differen- tiation between normal, reactive and malignant me sothelial cells is often dif \201 cult. Distinguishing malignant pleural mesothelioma from meta- static pleural carcinoma can be challenging, and usually requires immunostaining wit h a broad panel of markers e.g. calretinin, epithelial membrane antigen (EMA) etc. Prognosis The prognosis of mesothelioma is poor with a median survival of approximately 8 \200\22314 months although these \201 gures vary dependent on patient selection and how s urvival was calculated. Long-term survival (>5 years) has occasionally been reported. Perfo rmance status and histological subtype are the most important prognostic indicators. Epithe lioid mesothelioma has a better survival compared with biphasic and sarcomatoid Pleural biopsy If cytological analysis is inconclusive, pleural biopsy should be performed unless clinically contraindicated. H DAVIES & G LEE 348 subtypes. Staging of mesothelioma at presentation is also related to outcome with a shorter survival seen in those with advanced disease. Other, weaker, prognostic indicators, associ ated with an adverse prognosis, have been identi \201 ed and include age (>75 years), male gender, low hemoglobin, raised lactate dehydrogenase (LDH) and high white blood cell and p late- let counts. Clinically the presence of chest pain and >5% weight loss may suggest a w orse prognosis. Surgery As mesothelioma spreads along the serosal surface rather than growing as a de \201 ned mass, surgical attempts to eradi- cate mesothelioma have not been successful. No ran- domised controlled trials support the use of radical surgery (extrapleural pneumonectomy, E PP) in mesothelioma. EPP has an operative mortality of approximately 5%, and 25% of patient s suffer life-threatening complications. Pa- tients \200\231 quality of life is signi \201 cantly worsened for the \201 rst 6 months after EPP. Tumor relapse always occurs if pati ents survive long enough. Thoracic debulking with pleurectomy, as a palliative proce- dure, has not been fully assessed. Treatment There is no curative treatment for mesothelioma hence management should focus on providing symptom relief and improving patients \200\231 quality of life. A multi-disciplin ary team approach is recommended to ensure medical, psychologi- cal, \201 nancial and med icolegal support is provided for the patients and their families. Trimodality therapy As EPP alone does not provide a cure, trimodality therapy, i.e. EPP wit h adjuvant chemotherapy and radiotherapy, has been tried. Although patients are highly sele cted, with early stage disease, a good performance status and no significant co-morbidity, no definite survival benefit has been seen and the role of trimodality therapy remains unpr oven. Psychological support The psychological aspects of patients with mesothelioma deserve atten tion, as the issues involved differ from other cancers. Many patients have lived under the anxiety of developing the disease for decades and have witnessed death of previous colleagu es from mesothelioma. Amongst some, mesothelioma carries a reputation of horrible death of drowning and suffocation. Anger towards prior employ- ers for lack of provision of occupati onal protection is com- mon. Medicolegal proceedings often present additional stresses. Novel approaches Gene therapy and immunotherapy have both shown prom- ise in preliminary ph ase trials. No survival bene \201 t has been seen with photodynamic therapy. Anti-angiogen ic strategies and molecular targeted thera- pies are being explored. Analgesia Pain is a major issue for many patients. Opiate analgesia is often required and r adiotherapy can ease localized pain, e.g. from bone erosion or tract metastases. In severe and refractory cases percutaneous cervical cordotomy (interrupting the spinothalamic tract at C1 \200\223 C2), intrathecal analgesia and regional nerve blocks may be considered. Compensation (See Chapter 16.3) Patients with mesothelioma are often eligible for compen- s ation though eligibility and compensation regulations vary among countries. Prevention and screening in exposed individuals Anxiety of developing mesothelioma is high among the millions of workers exposed to asbestos worldwide. There is no proven prophylacti c therapy, though some evidence suggests that vitamin A may have some protective effect. No effective screening methods exist. The preliminary data on the use of mesothelin in predic ting disease develop- ment awaits validation in large studies. Population screen- ing canno t at present be justi \201 ed as no effective curative treatment exists and no evidence su ggests early detection alters outcome. Dyspnoea Pleural effusions from mesothelioma almost always recur. Early pleurodesis is reco mmended. In patients with tumor encasing the lung preventing re-expansion ( \200\230trapped lung \200\231) drainage with an ambulatory indwelling pleural catheter may be useful. Surg ical pleurodesis and, rarely, pleuroperitoneal shunting are alternative options. Radiotherapy There is no role for radical radiotherapy alone in mesothe- lioma. Various fra ctionation strategies (e.g. intensity modu- lated radiotherapy (IMRT)) are under investigat ion. Palliative radiotherapy can provide good pain relief for localized symptoms. Prophylac tic radiotherapy to sites of pleural intervention can reduce the risk of tract site metasta ses. However, the value of routine administration to all pleural puncture sites is currentl y debated. AUTHOR \200\231S TIPS \200 Suspect the diagnosis in all patients with prior asbes- tos exposure and an exudative pleur al effusion regard- less of the interval since exposure and exposure intensity. However, ab sence of exposure does not exclude diagnosis. The histological subtype of mesothelioma shou ld be identi \201 ed wherever possible as the biological behav- iour and prognosis differ. Focus management on symptom palliation and main- taining quality of life. Psychological su pport for patients and their families is important but often over- looked by clinicians. Chemotherapy Multi-targeted folate antagonists, e.g. pemetrexed diso- dium or raltitrexed, in combination with cisplatin have shown a survival advantage of approximately 3 months and may improve quality of life. No other chemotherapy regimes, given intravenously or intrapl eurally, have shown proven bene \201 t. CHAPTER 14.7 Malignant mesothelioma 349 Further reading Cancer Research UK. www.cancerresearchuk.org Jaurand M-C, Fleury-Feith J. R eview: Pathogenesis of Malignant Pleural Mesothelioma. Respirology 2005; 10: 2 \200\2238. Robinson BWS, Musk AW, Lake RA. Seminar : Malignant Mesothelioma. Lancet 2005; 366: 397 \200\223408. Scherpereel A, Lee YCG. Biomarkers for mesothelioma. Curr Opin Pulm Med 2007; 13:339 \200\223443. West SD, Lee YCG. Current Management of Malignant Pleural Musk AW, de Klerk NH, Ambrosini GL, et al. Vitamin A and cancer prevention I: observations in workers previously exposed to asbestos at Wittenoom, Western Australia. Int J Cancer 199 8; 75:355 \200\22361. Mesothelioma. Clin Chest Med 2006; 27: 335 \200\223354. A DEGRYSE & R LIGHT 350 14.8 Pleural effusions in systemic disease Pleural effusions are associated with a wide variety of systemic diseases with a very broad and wide range of pathophysiology and pleural \202 uid characteristics. The effu- sions can be either exudative or transudative depending on the disease process. Gastrointestinal, obstetric, cardiovascular, and collagen vascular diseases more commonly involve pleural ef fusions as disease manifestations and often pleural effusions are markers of disease severi ty. The highly vascular pleura is sensitive to derangements in capillary permeability from systemic in \202 ammation making the pleural space vulnerable to \202 uid accumulation. This chapter provides a brief and limited sample of the systemic diseases that are complica ted by pleural manifestations. abscess is a much more serious condition carrying with it a very high mortality rate. In on e series, pleural effusions were found in nearly 40% of these patients. The pancreatic absc ess must be surgically drained but no speci \201 c treat- ment is required for the pleural effusion. Chronic pancreatic pleural effusions can develop when a sinus tract forms betwee n a pseudocyst and the thoracic cavity. Men are more likely to develop a pancreaticopleural \201 stula. These create large effusions often occupying the entire hemithorax. Diagnosi s is con \201 rmed by abdominal CT revealing the pancreatic psuedocyst and the sinus tract . Gynaecologic conditions Gynaecologic conditions associated most commonly with pleural effus ions include ovarian hyperstimulation syn- drome (OHSS) and Meigs \200\231 syndrome. OHSS r esults from the overstimulation of the ovaries by hCG and the fertility drug clomiphene. Th e pathogenesis of OHSS is quite inter- esting. The leading hypothesis is that elevated leve ls of IL-6 and VEGF gain access to the systemic circulation and act as capillary permeabili ty factors thus creating the transuda- tive effusions. These effusions are most commonly ri ght sided but bilateral effusions are not uncommon. Withhold- ing the fertility medications is the treatment. Meigs \200\231 syndrome consists of a benign ovarian tumor, ascites, and pleural effusions. Transdiaphragmatic transfer of \202 uid is the proposed mechanism of the effusion. Treat- ment is surgical removal of the pelvic tumor. Gastrointestinal tract Pancreatitis, intraabdominal abscesses, esophageal perfora- tion, bi liary tract disease, and cirrhosis are the more com- mon gastrointestinal diseases associat ed with pleural effusions (Table 14.8.1). Both exudative and transudative effusions are enc ountered but exudative effusions are far more common. Table 14.8.1 Gastrointestinal disease overview Diagnosis Pleural effusion characteristics Pathophysiology Pancreatitis Most commonly bilateral; exudative, elevated amylase, elevated levels of phospholipase A2 Transdiaphragmatic transfer of exudative \202 uid from the pancreas. With pseudocyst get sinus tract from pancreas to pleural space Cardiovascular system Post-CABG pleural effusions are very commonly encountered. These are identi \201 ed in the vast majority of patients but nearly all are small and inconsequenti al. The large pleural effusions that do occur are divided into early (within 30 days post-o p) and late (after 30 days). More early effusions are associated with internal mam- mary gr afts vs saphenous vein grafts and with the use of topical hypothermia. The effusion is pred ominately left sided and the characteristic \202 uid is a bloody exudate with an eosinoph il predominance. The most common present- ing complaint is dyspnoea. The late post-op effus ions are clear non bloody exudates and lymphocytes dominate. Both early and late effusions will generally resolve without treatment but thoracentesis should be preformed to rule out other causes if the patient is febrile or has chest pain. A therapeutic thoracentesis shoul d be performed if the patient is experiencing dysp- noea. If the pleural effusion continues to reaccumulate a pleurodesis or VATS procedure may be necessary but this is rarely occurs . In \202 ammation of the diagphragm increasing its permeability Subphrenic abscess Effusions in 60 \200\22380% of cases; exudative and neutrophil predominance Acute mediastinitis causing medistinal pleural rupture Oesophageal perforation Subcutaneous emphysema often present; low pleural \202 uid pH, often accomopanied by pneu mothorax. mortali- ty approaches 60% Many patients with cirrhosis and ascites have small defects in their diaphragms. Low pressu re in pleural space sucks ascitic \202 uid into pleural space Cirrhosis Transudative; generally should not perform therapeutic thoracentesis as the \202 uid will reoccur Pancreatitis Pancreatitis associated pleural effusions are often bilateral, exudative and o ften bloody. The presence of an effusion in pancreatitis is a negative prognostic indicator . An effusion associated with simple pancreatitis need not require a tho- racentesis as lon g as the patient is not febrile. A pancreatic Collagen vascular diseases Collagen vascular diseases are occasionally complicated by pleur al effusions that are quite varied in their characteristics Table 14.8.2. CHAPTER 14.8 Pleural effusions in systemic disease 351 Table 14.8.2 Collagen vascular diseases Disease Incidence and patient characteristics Presentation Pleural \202 uid characteristics Treatment Most often the effusions resolve spontaneously No clinical trials available but recommendat ion is to treat with NSAIDS for 8 \200\22312 weeks Exudative Low glucose <20mg/dL Low pH <7.20 Often cholesterol crystals and elevated cholest erol level present Patients often present with pleuritic chest pain Small to moderate sized effusion Usually u nilateral but no predilection for either side Rheumatoid arthritis Between 3 \200\2235% of patients with RA More common in men with RA than women Subcutaneous rheumatoid nodules often present Very good response to systemic corticosteroids; recommendations: 80mg of prednisone every o ther day with rapid taper once clinical improvement is demonstrated Pleuritic chest pain common Usually small but can be large and occupy >50% hemithorax 50% b ilateral Serosanguinous Exudative Glucose level >80mg/dL pH above 7.20 Systemic lupus erythematosus Approximately 16% to 44% of patients More common in women than men Fluid not well characterized Cyclophosphamide and high dose steroids treat the underlying disease and the pleural effusi on will resolve Wegener \200\231s granulomatosis 22 \200\22355% present with small effusions Patients present with upper and lower respiratory tract involvement and glomerulonephritis; important to consider this disease in patients with parenchymal in \201 ltrates, nodules, and a pleural effusion. Need to measure ANCA Further reading Abramov Y, Elchalal U, Schenker JG. Pulmonary manifestations of severe ovar ian hyperstimulation syndrome: a multicenter study. Fertil Steril 1999; 71: 645 \200\223651 . Halla JT, Schronhenloher RE, Volanakis JE. Immune complexes and other laboratory features o f pleural effusions. Ann Intern Med 1980; 92: 748 \200\223752. Light RW. Pleural effusions after coronary artery bypass graft surgery. Curr Opin Pulm Med 2002; 8: 308 \200\223311. N MASKELL 352 14.9 Pleural infection Epidemiology Pleural effusions occur in up to 40% of patients with pneu- monia. Pleural inf ection affects patients of all ages but is more common in children and the elderly. Men are affected twice as often as women. Its incidence is higher in those with diabetes, alcoholi sm, substance abuse and chronic lung disease. Class 2 \200\223 typical parapneumonic: >10mm thick, glucose >40 mg/dl, pH > 7.2. \200 Class 3 \200\223 borderline complicated: pH 7.0-7.2 or LDH >1000 Gram stain negative. \200 Class 4 \200\223 simple complicated: pH < 7.0 or Gram stain positive. No loculation or frank pus. \200 Class 5 \200\223 complex complicated: 0 0 1 pH < 7.0 Gram stain positive. Loculations. \200 Class 6 \200\223 Simple empyema: 0 8 Frank pus, single locule or free \202 owing. \200 Class 7 \200\223 Complex empyema: Frank pus, multiple loculations. 0 6 y c n e u q e r F Differential diagnosis The commonest problem with the differential diagnosis is failure to make the correct positive diagnosis. Often the presentation is indolent (especially in the elderly) with weight loss and anorexia and little fever. Other possible causes for the effu sion include: \200 \200 \200 \200 0 4 0 2 0 18 \200\22324 25 \200\22334 35 \200\22344 45 \200\22354 55 \200\22364 65 \200\22374 75 \200\22384 85 \200\22394 Age group (years) Tuberculosis effusion. Malignancy. Rheumatoid pleural effusion. Pulmonary embolus with asso ciated effusion. Male Female Fig. 14.9.1 Empyema frequency. Etiology Associated conditions \200 The commonest causes of pleural infection are: \200 \200 \200 \200 \200 Lemierre \200\231s syndrome \200\223 acute oropharyngeal infection with Fusobacterium spec ies leading to septic throm- bophlebitis of the internal jugular vein, septic pulmonary emb oli and empyema. Secondary to a community-acquired pneumonia (70%). Secondary to a hospital-acquired pneumon ia (12%). Primary empyema (5%). Post operative (10%). Miscellaneous (bacteraemia, oesophage al rupture, IV drug abuse, abdominal infection/collection) (3%). Bacteriology This differs signi \201 cantly between pleural infection acquired in the comm unity and those acquire in the hospital setting. In view of this they require different emp irical antibiotics. In one large randomized trial throughout the UK the following bacteria were cultured: Pathophysiology This can be divided into three stages \200 The development of the initial effusion is due to increased permeability of the pleural membranes. Fluid moves into the space owing to lo cally increased capillary vascular permeability. The accumulating pleural \202 uid has a normal glucose level and pH. \200 Secondary bacterial invasion occurs and the high level of \201 brinolytic activity in the pleural space is suppressed and tissue plasminogen act ivator inhibitor 1 and 2 rise. This leads to \201 brin deposition over the visceral and p arietal pleura and loculations form. Bacterial metabolism lead to increased lactic acid pro duction and fall in pH. \200 Proliferation of fibroblasts and evolution of pleural scarri ng. An inelastic peel forms on both pleural surfaces with dense \201 broid septations. As solid \201 brous peel replaces the soft \201 brin lung function is impaired. The exudative phase Community acquired \200 \200 \200 \200 \200 \200 \200 \200 S. Milleri group (32%). Streptococcus pneumoniae (13%). Other Streptococci (7%). Staphyloco cci (11%). Anaerobes (16%). Enterobacteriaecea (7%). Proteus (3%). H. in \202 uenzae (3%). The \201 bropurulent phase Hospital acquired \200 MRSA (26%). \200 Staphylococci (18%). \200 Enterobacteriacea ( 16%). \200 Enterococci (13%). \200 Pseudomonas (5%). \200 Streptococci (10%). The organizing stage Classi \201 cation Light \200\231s classification of parapneumonic effusions and empyema \200 It should be noted that up to 40% of patients with pleural infection do not ever have a pos itive bacterial culture. This is partly due many having already started antibiotics before hospital presentation. Class 1 \200\223 non signi \201 cant: Small <10 mm thick. No thoracentesis required. CHAPTER 14.9 Pleural infection 353 Investigations Pleural \202 uid sampling Fluid should be sent to the laboratory for gluco se, LDH and protein measurements as well as standard cytological and microbiological invest igations. A sample of \202 uid (not frank pus) should also be placed in a heparinised syr inge and the pH measured CT \200 Useful in trying to distinguish a lung abscess from a pleu- ral collection. Also helpful in evaluating the drain position and any residual location in a patient not responding to med ical treatment where surgery is being contemplated. With a contrast CT, as with other exuda tive effusions, pleural enhancement is seen. Imaging The imaging features of parapneumonic effusion and empy- ema depend upon the state of evolution of the effusion and the underlying etiology. The imaging will also often have to be circumstance led, e.g. a ultrasound for ill unstable patients on ITU. Differentiating between a lung abscess and empyema on enhanced CT. The following rules are often useful in distinguishing a lung abscess for an empyema: Lung abscess \200 \200 \200 Chest radiology \200 Often round in shape. Vessels passing through or near. Indistinct boundary between lung par enchyma and collection. Thick and irregular wall, making contact with chest wall at acute a ngle. In general, a pleural effusion is demonstated often in association with consolidation. The effusion is commonly unilateral. If uncomplicated it behaves like a non-infected sterile ef fusion with a normal meniscus sign. If complicated it may be loculated. It will then have a lentiform, pleural based opacity. If the effusion is within a \201 ssure it may have the appearance of a \200\230pseudotumour \200\231. Empyema \200 \200 \200 \200 Lenticular in shape. No vessels closely associated. Compression of surrounding lung. Smooth margins creating obtuse angles, following contours of chest. Fig. 14.9.2 CXR of a loculated empyema. Ultrasound \200 Fig. 14.9.4 Loculated empyema on CT. The majority of parapneumonic effusions will be septated and may be hyperechoic. Whereas se ptations are readily visualized on ultrasound, pleural thickening is poorly visualized and CT is better. Treatment AUTHOR \200\231S TIP \200 A complicated parapneumonic effusion due to Proteus spp. does not result an acidic effusion . The pH of the pleural \202 uid should be measured (using an arterial blood gas machine and heparinised syringe) in all cases of suggested parapneumonic effusions. This should not be done with frank pus as it will damage the machine. A pH <7.2 is an indication that form al tube drainage will be required. Antibiotics As the microbiology is very different between community- acquired and hospital- acquired pleural infection they require different empirical antibiotic regimens at presenta tion. Possible empirical antibiotic regimens: \200 \200 Community acquired \200\223 co-amoxiclav and metronidazole. Hospital acquired \200\223 me ropenem and vancomycin. Fig. 14.9.3 Pleural ultrasound showing loculations. N MASKELL 354 The role of other \201 brinolytics are still being evaluated and the MIST 2 trial should be reporting shortly.