Obesity* Scoliosis* Post thoracoplasty (usually \200\230three stage \200\231, many ribs ca ved in starting from the top down \200\224done for tuberculosis prior to effective chemothe rapy) Flail chest Pneumothorax/large effusion Severe ankylosing spondilitis \200 \200 Airways obstruction/mixed \200 \200 Unrecognized COPD/severe asthma* Obstructive sleep apnoea and additional COPD/obesity/muscl e weakness*, sometimes called \200\230overlap syndrome \200\231. The ventilatory loading effects of obesity, COPD, and OSA can summate to produce ventilator y failure, when on their own they would not be regarded as of suf \201 cient severity. Est imating the contribution each is making to an individual \200\231s ventilatory failure can in \202 uence therapy, and expectations of success: e.g. if OSA dominant (>4% SaO2 dips/h >30) the ventilatory failure is likely to respond to CPAP; dominant COPD (FEV1 <25% predict ed) will need maximal lower airways dilator therapy (thresholds only for general guidance); but the likely poor response of the lower airways obstruction will mean that even limited additional weight reduction, and/or treatment of milder OSA, may be useful in the latter si tuation. CHAPTER 15 Unexplained ventilatory failure 94 Clinical presentation Slow onset In several of the above conditions, e.g. acid maltase de \201 ciency, MND, and scoliosis, the onset of ventilatory failure can be insidious and incl ude: \200 \200 \200 \200 \200 \200 General fatigue and/or hypersomnolence Headaches on awakening Morning confusion Morning cya nosis Ankle oedema ( \202 uid retention, cor pulmonale, from the hypoxia). Dyspnoea standi ng in the swimming pool (this usually indicates diaphragm paralysis, as pressure of water, even at 1 m depth, pushes unopposed diaphragm further up into the chest) Swallowing dif \201 culties (often MND), or other evidence of a more generalized proximal neuromuscular pr oblem. Rapid onset Sometimes the signi \201 cance of these symptoms is missed for a while and a r elatively trivial respiratory tract infection tips the balance and the patient goes into se vere ventilatory failure with coma. These individuals will end up ventilated on ICU and may be dif \201 cult to wean, or present again with ventilatory failure a few weeks after dis charge. Further information Resta O et al. Sleep-related breathing disorders, loud snoring and exce ssive daytime sleepiness in obese subjects. Int J Obes Relat Metab Disord 2001; 25: 669-75 This page intentionally left blank CHAPTER 15 Unexplained ventilatory failure 96 Clinical assessment and management History, examination, and investigations History Careful ly taken history, e.g. symptoms of subtle weakness prior to presentation, episode of should er pain (neuralgic amyotrophy), past history of polio, orthopnoea (diaphragm weakness), dru g history. Often this is not available as the patient may present unconscious. Examination Thorough examination, particularly neurological, e.g. fascicu- lation, diaphragm weakness ( inward drawing of abdomen on inspiration or snif \201 ng \200\224masked if on positive pre ssure ventilation), myotonia, as well as rarer signs seen in some of the conditions listed previously. Blood gasses taken breathing air (following >20 min off extra O2) \200 \200 \200 \200 Degree of CO2 retention Presence of a base excess indicating chronicity of CO2 retention Ca lculate A \200\223a gradient to detect any V/Q mismatch (p 792) In pure hypoventilation the re should be no signi \201 cant A \200\223a gradient (<2 kPa), unless there is associated basal atelectasis from poor lung expansion and/or obesity. Pulmonary function tests (p 827) \200 \200 \200 Presence of unexpected severe airways obstruction Reduced vital capacity (neurological or c hest wall) Further fall of VC (>20% de \201 nitely abnormal) on lying down \200\224 indica tive of diaphragm paralysis. A supine VC of <25% predicted is most predictive of this being the main cause of the raised PaCO2. Mouth pressures, sniff pressures, or trans-diaphragmat ic pressures; not much more helpful than lying and standing VC. Speci \201 c tests \200\224for some of the conditions listed above such as: \200 \200 \200 \200 EMG studies \200\223MND, myotonia MRI \200\223Gadolinium enhanced: Arnold \200\223Chiari, b rainstem lesion, syrinx CPK \200\223Some myopathies Sleep study \200\223E.g. (i) REM hypoxi a (early marker of ventilatory failure when supine VC usually has dropped below 60% predict ed normal), (ii) continuous nocturnal hypoventilation (when supine VC has dropped below 40% predicted), and (iii) obstructive sleep apnoea Blood \201 lm for abnormal lymphocyte cyt oplasmic vacuolation (mainly acid maltase de \201 ciency) Muscle biopsy \200\223acid malta se de \201 ciency (glycogen-containing vacuoles and low enzyme levels). Management of the underlying condition, if available, is paramount. Weak expiratory muscles and weak laryngeal adduction prevent effective coughing with an increased incidence of ser ious chest infections. Clearing retained secretions can be a major problem. Physiotherapist s can help teach patients and their carers sputum clearance techniques. Increasing the lung volume with positive pressure devices (e.g. the Bird device) and \200\230breath stacking \200\231 allows a higher expiratory \202 ow with improved clearance. Mechanical insuf \202 ator/exsuf \202 ator devices are available that both increase inspiratory volume and speed expiratory \202 ows. Their role is still being evaluated. CLINICAL ASSESSMENT AND MANAGEMENT 97 Lying down and sleeping with the whole bed tipped head up by about 20* greatly improves ven tilation in the presence of bilateral diaphragm paralysis. Just elevating the top half of t he bed, leaving the abdomen and legs horizontal, does not work. The abdominal contents have to descend into the pelvis to effectively \200\230of \202 oad \200\231 the diaphragm. Th is posture will also improve the ability to wean from assisted ventilation. In the situation of irreversibility, the decision will need to be taken as to whether non-invasive ventilation is appropriate (p 693). This page intentionally left blank Part 00 Part 2 Clinical conditions 16 Acute respiratory distress syndrome 17 Asbestos and the lung 18 Asthma 19 Bronchiectasis 20 Bronchiolitis 21 Chronic obstructive pulmonary disease (COPD) 22 Connective tissue dise ase and the lung 23 Cor pulmonale 24 Cystic \201 brosis 25 Eosinophilic lung disease 26 E xtreme environments: \202 ying, altitude, diving 27 Gastrointestinal disease and the lung 28 Hypersensitivity pneumonitis 29 Hyperventilation syndrome 30 Idiopathic interstitial pn eumonias 31 Lung cancer 32 Lung transplantation 101 107 121 149 159 165 185 201 205 227 235 243 249 255 259 279 317 33 Mediastinal abnormalities 34 Pediatric lung disorders pertinent 331 339 to adult patients 35 Pleural effusion 36 Pneumoconioses 37 Pneumothorax 38 Pulmonary hypert ension 39 Pulmonary thromboembolic disease 40 Respiratory infection: bacterial 41 Respirato ry infection: fungal 42 Respiratory infection: mycobacterial 43 Respiratory infection: para sitic 44 Respiratory infection: viral 45 Sarcoidosis 46 Sickle cell disease: pulmonary comp lications 47 Sleep apnoea and hypoventilation 48 Toxic agents 49 Unusual conditions (BOLD) 50 Upper airway diseases 51 Vasculitis and the lung 345 363 373 385 401 419 465 487 523 529 547 561 567 593 609 639 649 101 Chapter 16 Acute respiratory distress syndrome Pathophysiology and diagnosis 102 Management and complications 104 CHAPTER 16 Acute respiratory distress syndrome 102 Pathophysiology and diagnosis De \201 nition and epidemiology ARDS (previously shock lung) is not a single entity, but represents the severe end of a spectrum of acute lung injury d ue to many different insults. Essentially it is: \200 \200 \200 Acute, persistent, lung in \202 ammation, increased vascular permeability Bilateral and ex tensive in \201 ltrates on the CXR Very poor oxygenation despite PEEP with variable ways o f de \201 ning the severity of this. PaO2/FiO2 ratio <27 using kPa, or <200 using mmHg. e. g. PaO2 only 10 kPa on 0.60 (60%) O2, ratio = 16.7, therefore <27 Not due to clinical left ventricular failure or associated with a wedge pressure of over 18 mmHg (i.e. non-cardiogen ic) Most commonly seen on the ITU where about 10% of such patients will have ARDS depending on the de \201 nition. \200 The Murray lung injury score, grading ARDS, is based on plain CXR \201 ndings, oxygenatio n, PEEP level, and respiratory system compliance (see p 105). Pathophysiology In \202 amma tory damage to the alveoli, either by locally produced pro-in \202 ammatory mediators, or remotely produced and arriving via the pulmonary artery. The change in pulmonary capillary permeability allows \202 uid and protein leakage into the alveolar spaces with pulmonary in \201 ltrates. The alveolar surfactant is diluted with loss of its stabilizing effect, r esulting in diffuse alveolar collapse and stiff lungs. This leads to: \200 Gross impairment of V/Q matching with shunting causing arte- rial hypoxia and very large A \200\223a gradients. There are usually enough remaining functioning alveoli such that a deg ree of hyperventilation maintains CO2 clearance; thus hypercapnia is infrequently a problem Pulmonary hypertension will develop secondary to the hypoxia, but this is probably helpful (aids V/Q matching), rather than deleterious Reduced compliance (stiff lungs) due to loss of functioning alveoli (alveolar collapse, \201 lled with \202 uid and protein) and hyp erin \202 ation of remaining alveoli to their limits of distension. There are many causes of pro-in \202 ammatory mediator release suf \201 cient to cause AR DS and there may be more than one present. Common causes in order of prevalence: \200 Sepsis/pneumonia; secondary risk factors for developing ARDS, when septic, are alcoholism a nd cigarette smoking Gastric aspiration (even if on a proton pump inhibitor, indicating tha t a low pH is not the only damaging component) Trauma/burns, via sepsis, lung trauma, smoke inhalation, fat emboli, and possibly direct effects of large amounts of necrotic tissue. Less common causes \200 Transfusion-related acute lung injury (TRALI), caused by any blood product (possibly due to HLA/white blood cell antibodies, commoner with older blood products, >6 units); usually oc curs within a few hours of transfusion. No speci \201 c therapy or evidence of steroid res ponse Transplanted lung \200\224worse if the lung poorly preserved PATHOPHYSIOLOGY AND DIAGNOSIS 103 \200 \200 \200 \200 \200 Post-bone marrow transplant as bone marrow recovers Drug overdose, e.g. tricyclic antidepre ssants, opiates, cocaine, aspirin Acute pancreatitis Near drowning Following upper airway o bstruction; mechanism unclear Acute form of UIP/CFA. Also called AIP and used to be known a s acute Hamman \200\223Rich syndrome (p 272). The course of ARDS is fairly characteristic Phase 1 is the early period of alveolar damage and hypoxaemia with pulmo- nary in \201 ltration. Phase 2 develops after a week or so as the pulmonary in \201 ltrates resolve, and on histo logy seems to be associated with an increase in type II pneumo- cytes (surfactant producers ), myo \201 broblasts, and early collagen formation. Phase 3 if the patient survives, is the \201 brotic stage that leaves the lung with cysts , deranged micro-architecture, and much \201 brosis on histology. Clinical features ARDS should be considered in any patient with a pre- disposing risk factor who develops severe h ypoxaemia, stiff lungs, and a widespread diffuse pulmonary in \201 ltrate. Approximately 1 \200\2232 days following the clinical presentation of the precipitating cause (sepsis, asp iration, etc.), there is rapidly worsening dyspnoea (9 a dry cough) and hypox- aemia, requi ring rapidly escalating amounts of supplemental oxygen up to 100% via a non-rebreathe syste m (p 704). Coarse crackles in the chest. Intubation and ventilation are nearly always requi red, although initiating CPAP via a face-mask at 5 \200\22310 cmH2O with 100% O2 can improv e oxy- genation temporarily. Diagnosis There are no speci \201 c tests that allow a con \201 dent diagnosis, and exclusion of other more speci \201 cally treatable diagnoses is r equired. The cause for the ARDS needs to be established and prevented from con- tinuing or reccurring if possible. The CXR or CT show diffuse alveolar in \201 ltrates and air bronch ograms, similar in appearance to cardiogenic pulmonary oedema or diffuse pulmonary hemorrha ge. Left ventricular failure may be excluded on clinical grounds or by echocardiography, bu t con \201 dent exclusion requires a wedge pressure measurement less than 18 mmHg. Diffuse alveolar hemorrhage can occur in Goodpasture \200\231s, Wegener \200\231s, and SLE; clues will include a drop in hemoglobin, blood in the airways and pulmonary secretions, and other clinical features of one of these disorders. Some pulmonary infections (e.g. mycobacteria, Legionella, PCP, viral pneumonia) may mimic ARDS and lavage \202 uid may reveal these. S ome centers advocate lung biopsy to exclude alternatives, although the diagnostic yield is very low if a lavage is negative. Occasionally, cancer and lymphangitis carcinomatosa can a lso mimic ARDS, and these will show on a lung biopsy. CHAPTER 16 Acute respiratory distress syndrome 104 Management and complications Management The essential aspects of management are to treat th e pre- cipitating cause, provide best supportive care with adequate oxygenation, and avoid further damage from barotrauma, hyperoxia, and nosocomial infections. Mechanical ventilatio n with PEEP and high in \202 ation pressures are almost always required to maintain oxygen ation (%SaO2 values in the low 90s are entirely adequate). There is some evidence that high in \202 ation pressures may worsen ARDS directly (micro-barotrauma); therefore, try to ma intain plateau pressures <30 mmHg. Many special ventilation techniques have been tried to reduce the high in \202 ation press ures that result from the stiff lungs (low compliance). For example, using low tidal volume s to reduce in \202 ation pressures (6 mL/kg ideal body weight compared with 12 mL/kg) red uces mortality by 10%. Reducing the minute ventilation and allowing the PaCO2 to rise (perm issive hypercapnia), also reduces the in \202 ation pressures. Prone ventilation has been tried in an attempt to improve V/Q matching and initial increase s in PaO2 are observed, but with no apparent effect on survival. Several different arti \201 cial surfactants have been tried to try and improve lung compl iance, although good delivery to the abnormal areas is unlikely. Although effective in anim al models, the RCTs have been negative in humans. Different degrees of hydration have been compared, with reduced \202 uid balances improvi ng gas exchange, but again with no impact on survival (but no harm either). High-dose steroids have been used, but there is evidence of harm as well as bene \201 t, a nd minimal evidence of overall improved survival. A recent meta-analysis concluded there wa s no overall signi \201 cant bene \201 t, but certain subgroups may do slightly better an d others worse: e.g. steroids are possibly bene \201 cial during the \201 rst 14 days, b ut detrimental thereafter. A recent RCT (total n = 91) on prolonged methylprednisolone infu sion (1 mg/kg/day) for early ARDS (<72 h) showed improvement in a number of outcomes and ha lved mortality. Extracorporeal oxygenation/CO2 removal will buy time and allow the lung to \200\230rest \200\231, but these techniques are very expensive and it is dif \201 cult to demonstrate a ny long-term bene \201 t. Complications of ARDS include: \200 The high ventilation pressures lead to barotrauma: pneumothorax, surgical emphysema, pneumo mediastinum. Pneumothorax may be lethal, but dif \201 cult to detect on a CXR in the supin e patient Nosocomial infections occur in about half the patients, making surveillance bronc hoalveolar lavage important Myopathy associated with long-term neuromuscular blockade, high steroid doses, and poor glycaemic control Non-speci \201 c problems of venous thromboembo lism, GI hemorrhage, inadequate nutrition. MANAGEMENT AND COMPLICATIONS 105 Prognosis has improved over the last 20 years, probably due to improve- ments in supportive care rather than an ability to modify the in \202 ammatory process and its subsequent rep air. Prognosis is worse with intra-pulmo- nary causes. Early deaths are usually due to the precipitating condition, and later deaths to complications. Over half the patients will sur vive with varying residual lung damage, although the pulmonary function tests often show on ly minor restrictive abnormalities (and reduced kCO), indicating the considerable capacity of the lung to recover. Future developments \200 The optimal level of PEEP in a particular patient is dif \201 cult to predict. Inadequate PEEP allows more atelectasis, but too high PEEP contributes to over-distension of remaining alveoli and further barotrauma when there are no more \200\230recruitable \200\231 alveol i. Ways to estimate the best PEEP are under investigation. High-frequency ventilation has b een around a long while, but its place in ARDS is still unclear. More recently, liquid vent ilation with per \202 uorocarbons has been tried. These dense oxygen- carrying liquids red uce the heterogeneity of ventilation by nullifying the requirement for surfactant, thus rec ruiting the collapsed alveoli. There are improvements in oxygenation but no evidence yet of increased long-term survival. Nitric oxide (NO) has been tried with clear improvements in oxygen- ation, but very little effect on survival. The mode of action is not clear and may be more than just vasodilatation. Inhaled prostacyclin is simi- larly unconvincing. Anti-in \202 ammatory and anti-oxidant therapies are still very much in the experimental phase. T here are current trials looking at low-dose inhaled carbon monoxide as an anti-in \202 amm atory. Biomarkers from either blood or bronchoalveolar lavage are being investigated as to their potential to predict steroid responsiveness (e.g. procollagen). \200\230Off the shel f \200\231 arti \201 cial lung systems are now becoming clinically useful to buy time whil e the lungs recover. The Novalung is an example, but such therapy is very expensive. Further information Murray ARDS score calculation, www.cesar-trial.org (Scroll down to just above \200\230Cesar site contents \200\231) Ef \201 cacy and safety of corticosteroids for persistent acute respiratory distress syndr ome. NHLBI ARDS clinical trials network. NEJM 2006; 354: 1671 \200\22384 Slutsky AS and Hudson LD. PEEP or no PEEP. NEJM 2006; 354: 1839 \200\22341 Wheeler A and Bernard G. Acute lung injury and the acute respiratory distress syndrome: a c linical review. Lancet 2007; 369: 1553 \200\22364 Meduri GU et al. Methylprednisolone infusion in early severe ARDS: results of a randomized con- trolled trial. Chest 2007; 131: 945 \200\2236 http://medgadget.com/archives/2007/02/novalung_ila_me.html (Novalung) This page intentionally left blank 107 Chapter 17 Asbestos and the lung Asbestos 108 Benign asbestos-related pleural disease 110 Asbestosis 112 Mesothelioma: diagn osis 114 Mesothelioma: treatment and outcome 116 Compensation for asbestos-related diseases 118 CHAPTER 17 Asbestos and the lung 108 Asbestos Asbestos consists of a family of naturally occurring hydrated silicate \201 bres that may be subdivided into two groups: \200 Curly serpentine \201 bres, of which chrysotile (white) is the only \201 bre currently in commercial use Straight needle-like amphiboles, which comprise crocidolite (blue), amosi te (brown), anthophyllite, tremolite, and actinolite Fibers differ in their lung clearance kinetics and pathogenic potential; amphibole \201 b res clear more slowly from the lung and are more carci- nogenic than chrysotile. Whilst asb estos usage in developed countries is restricted, the use of chrysotile asbestos in develop ing economies con- tinues to rise. Mechanisms of exposure Occupational exposure accounts for the majority of cases of asbestos - related disease and includes: \200 \200 Mining, milling, and transportation of asbestos Use of asbestos products, e.g. in construct ion and demolition, \202 oor tiling, insulation, \201 reproo \201 ng, textiles, fricti on materials (brake linings), ship building, pipe \201 tting, electrical repair, boiler \201 tting and lagging, carpentry, plumbing, and welding. Domestic exposure may include: \200 Relatives of asbestos workers exposed to \200\230carry home \200\231 asbestos in hair or c lothes Following remodeling or renovation in contaminated buildings Local geological exposu re from natural deposits, e.g. areas of central and south-east Turkey, north-west Greece, a nd Corsica Urban environment (although undisturbed and non-friable asbestos building insula tion is not considered hazardous). \200 A complete occupational history is essential if asbestos-related disease is suspected, and should include the method of exposure with dates and names of employers. This information m ay be of medico-legal importance and ideally should be elicited during the \201 rst consu ltation. Asbestos-related lung disease comprises: \200 Benign asbestos-related pleural disease \200 \200 \200 \200 Asbestosis Mesothelioma Lung cancer. Pleural plaques Benign asbestos-related pleural effusion Diffuse pleural thickening Rounded atelectasis \200 \200 Other diseases linked to asbestos exposure include pericarditis and, perhaps, head and neck , and gastrointestinal cancers. Whether asbestos exposure truly leads to an increased risk of lung cancer in the absence of asbestosis remains controversial. ASBESTOS 109 Asbestos-related disease typically exhibits a long latency period of 20 \200\22340 years fr om exposure. Peak industrial asbestos use in the UK occurred in the early 1970s, and asbest os-related disease is likely to remain common for at least the next 20 years. The incidence of mesothelioma is forecast to peak in 2015 \200\2232020 in Europe. All deaths should be noti \201 ed to the coroner if asbestos-related disease is suspected or proven. CHAPTER 17 Asbestos and the lung 110 Benign asbestos-related pleural disease Pleural plaques \200 \200 Most common manifestation of asbestos exposure Discrete areas of white or yellow thickening on the parietal pleura; may calcify Bilateral and occur particularly on the posterolateral chest wall, over the mediastinal pleura, and on the dome of the diaphragm Develop 20 \200 \22330 years after exposure; incidence (but not the extent of plaques) increases with longe r duration of exposure; found in up to 50% of asbestos-exposed workers and may also occur a fter low-dose exposures Usually asymptomatic, although if extensive may be associated with mild breathlessness due to pleural restriction Effect on pulmonary function is uncertain: m ost studies have failed to demonstrate abnormal lung function, although otherwise unexplain ed mild airways obstruction or restriction has been described in some populations of asbest os workers with pleural plaques \200\224the mechanism of this is unclear, although it may r e \202 ect asbestos-induced small airway disease or early interstitial \201 brosis, resp ectively HRCT is more sensitive than CXR in detecting pleural plaques There is no evidence that plaques are pre-malignant No longer eligible for compensation (p 118) Tuberculosis, tr auma, and haemothorax may each cause single pleural plaques; multiple plaques are highly su ggestive of asbestos exposure, however. \200 \200 \200 Benign asbestos-related pleural effusions \200 Relatively early manifestation of asbestos pleural disease; usually occurs within 10 years of exposure Development is considered to be dose-dependent, although can occur after minima l exposure Typically small and unilateral, and may be asymptomatic or occasionally associat ed with pleuritic pain, fever, and dyspnoea Usually resolve spontaneously over a few months , although some recur The pleural effusion is an exudate, often bloodstained, with no chara cteristic \201 ndings on pleural \202 uid analysis Diagnosis depends on a history of as bestos exposure and the exclusion of other causes, including mesothelioma Benign asbestos p leurisy may precede the development of diffuse pleural thickening; there is no clear associ ation with mesothelioma Treat symptomatically, with pleural aspiration for breathlessness a nd NSAIDs for pain. \200 BENIGN ASBESTOS-RELATED PLEURAL DISEASE 111 Diffuse pleural thickening (DPT) \200 Consists of extensive \201 brosis of the visceral pleura with areas of adhe- sion with th e parietal pleura and consequent obliteration of the pleural space Unlike pleural plaques, its margins are ill-de \201 ned, and it may involve the costophrenic angles, apices, and i nterlobar \201 ssures Development appears to be dose-related and may follow recurrent asb estos pleurisy On CXR, it may be de \201 ned as a smooth uninterrupted pleural opacity ext ending over at least a fourth of the chest wall, with or without obliteration of the costop hrenic angles; on CT, the pleural density extends more than 8 cm craniocaudally, 5 cm later ally, and is more than 3 mm thick Symptoms are relatively common and comprise exertional br eathless- ness and chest pain, which can be chronic and severe May lead to signi \201 cant restrictive pulmonary function impairment, especially if the costophrenic angle is obliter ated; hypercapnic respiratory failure has been described Pleural biopsy may be required to distinguish it from mesothelioma Treatment is dif \201 cult; decortication often fails to result in clinical or functional improvement Patient may be eligible for compensation (see p 118). \200 Rounded atelectasis (also known as folded lung, Blesovsky syndrome, or shrinking pleuritis with atelectasis) \200 Develops as contracting visceral pleural \201 brosis; ensnares and then twists the underl ying lung, resulting in the distinctive radiological appearance of a rounded or oval pleura l-based mass of 2.5 \200\2235 cm in diameter Asbestos exposure is the most common cause, al though any cause of pleural in \202 ammation may result in rounded atelectasis CT is often diagnostic, demonstrating a \200\230comet tail \200\231 of vessels and bronchi converging toward the lesion, adjacent thickened pleura, and volume loss in the affected lobe An atyp ical appearance may require biopsy to exclude malignant disease Typically asymptomatic, alt hough breathlessness or dry cough may occur Usually stable or slowly progressive, and no sp eci \201 c treatment is required Surgical decortication may improve symptoms, but frequent ly results in reduced lung volumes and is not generally recommended. Further information American Thoracic Society Statement:. Diagnosis and initial management of non-malignant dis- eases related to asbestos. AJRCCM 2004; 170: 691 \200\223715. CHAPTER 17 Asbestos and the lung 112 Asbestosis De \201 nition Chronic interstitial \201 brosis resulting from asbestos inhal ation. Causes Factors affecting disease development include: \200 Degree and length of asbestos exposure \200\224a clear dose \200\223response relationship e xists; usually seen in workers with many years of high exposure, although may follow a very high exposure of short duration, resulting in a shorter latency period Fiber type \200\224 amphibole \201 bres are probably more \201 brogenic than chrysotile, although most expo sures are mixed \201 bre types Cigarette smoking increases the severity and rate of progr ession of asbestosis. Latency period from \201 rst exposure to clinical disease is usually at least 15 \200\223 20 years and may be >40 years. Clinical features Insidious onset of breathlessness, dry cou gh. Bibasal late-inspiratory crackles, clubbing in 40% of cases. May progress to respira- t ory failure, cor pulmonale. Differential diagnosis includes other causes of interstitial \201 brosis, particularly usual interstitial pneumonitis (UIP). Investigations \200 CXR Bilateral symmetrical reticulonodular pattern, primarily affecting the lower lobes peri pherally, which may extend upwards to involve the mid and upper zones; may progress to hone ycomb lung. Massive bilat- eral upper lobe \201 brosis (without lower lobe involvement) i s rare, but well described. Associated pleural thickening or plaques may be seen, and sugge st a diagnosis of asbestosis, rather than UIP. Classi \201 cation is based on size, thickn ess, and profusion of opacities. CXR insensitive to early disease; may be normal in 15 \200 \22320% of symptomatic biopsy-proven asbestosis HRCT is more sensitive than CXR and is abno rmal in 10 \200\22330% of cases with a normal CXR. Features include basal \200\230ground-g lass \200\231 opacities (seen early in the disease), parenchymal bands, subpleural curvilin ear lines and opacities, interlobular septal thickening, and signs of \201 brosis (tracti on bronchiectasis, loss of lobular architecture, honeycombing in advanced disease) PFTs are classically restrictive with reduced lung volumes and transfer factor, although obstructiv e or mixed patterns may also occur (perhaps re \202 ecting asbestos-induced small airway d isease) Positive gallium scan may be seen with normal CXR; correlates poorly with lung func tion Analysis of sputum or bronchoalveolar lavage may demonstrate asbestos bodies, although sensitivity is limited. The \201 nding of interstitial \201 brosis in the absence of a sbestos bodies on lung biopsy makes asbestosis unlikely. Analysis of material for asbestos bodies is only very rarely indicated, usually for research or litigation purposes. ASBESTOSIS 113 In general, CXR and HRCT show only limited correlation with physiolog- ical disease severit y. Diagnosis Gold standard is pathological demonstration of \201 brosis with mineralogica l quanti \201 cation of asbestos bodies; in practice this is rarely required and a diagnos is can be made on the basis of a history of signi \201 cant asbestos exposure with appropr iate delay between exposure and disease, and radiographic evidence of \201 brosis. Treatment \200 \200 No pharmacological treatment is of proven bene \201 t Supportive management, including sup plementary oxygen as required, in \202 uenza and pneumococcal immunization, smoking cessat ion, compen- sation if exposure was occupational (p 118). Prognosis varies widely. After removal from exposure, progression occurs in 5 \200\22340% o f patients over 10 years; progression is faster following greater exposure, although rapid progression over 1 \200\2232 years is unusual and more in keeping with UIP. Fewer CXR opaci ties after exposure are associated with better prognosis. Increased risk of developing lung cancer. CHAPTER 17 Asbestos and the lung 114 Mesothelioma: diagnosis De \201 nition Malignant tumor of serosal surfaces (most commonly the pleura) usually resulting from asbestos exposure. Causes Asbestos is the major single c ause and there is a history of occu- pational asbestos exposure in up to 90% of cases. All types of asbestos can cause mesothelioma \200\224amphibole is the most potent, but also evi - dence for chrysotile. Mean latent interval between \201 rst exposure and death is aroun d 40 years; cases with latency <15 years are rare. Not dose- related (unlike asbestosis or bronchogenic cancers) and no evidence for a threshold asbestos dose below which there is no risk, although the risk at low exposure levels is small. No signi \201 cant association w ith smoking. The mechanism through which asbestos \201 bres result in mesothelioma is unc lear; possibilities include direct irritation of the parietal pleura, disrup- tion of mitos is, generation of toxic oxygen radicals, and stimulation of mitogen-activated kinases leadi ng to proto-oncogene activation. Other causes of mesothelioma include non-asbestos \201 bres, such as erionite, which is f ound in rocks in Cappadocia, Turkey \200\224mesothelioma accounts for up to a fourth of all adult deaths in local villages. Evidence for simian virus 40 (contaminated polio vaccine i n 1950s/60s) is limited. Rare cases of mesothelioma caused by ionizing radiation or chest i njury are described. \200\230Spontaneous \200\231 mesothelioma in children is also documen ted. Clinical features of pleural mesothelioma: \200 Chest pain (typically dull ache, \200\230boring \200\231, diffuse, occasionally pleuritic) , breathlessness; a small proportion are asymptomatic. Profuse sweating may occur Consider in any patient with a pleural effusion or pleural thickening, particularly if chest pain is present Rarely may present with persistent chest pain and a normal CXR Weight loss and fat igue uncommon at presentation (<30% of cases) Clubbing is very rare (<1%) Chest wall invasi on may be seen (especially at thoracentesis sites) Bilateral pleural involvement is unusual at presentation Paraneoplastic syndromes are described, e.g. disseminated intravascular co agulation. \200 \200 \200 \200 \200 Differential diagnosis includes benign asbestos pleural effusion, diffuse pleural thickenin g, and adenocarcinoma involving the pleura. Investigations 1. Pleural \202 uid aspiration typically reveals an exudative straw-colore d or bloody effusion. Cytological analysis may provide the diagnosis (sen- sitivity ranges 32 \200\22384%), and is often useful in excluding other pathology, e.g. adenocarcinoma. Ple ural \202 uid glucose and pH may be low in extensive tumors. Mesothelioma may track throu gh the chest wall along thora- cocentesis sites; avoid repeated pleural aspiration if the d iagnosis is sus- pected, and \200\230tattoo \200\231 aspiration sites with indelible ink t o guide subsequent prophylactic radiotherapy. MESOTHELIOMA: DIAGNOSIS 115 2. Imaging CXR and CT features include: \200 Moderate to large pleural effusion, usually with pleural nodularity and enhancement followi ng pleural contrast and involvement of mediastinal pleura Localized pleural mass or thicken ing without free \202 uid Uniform encasement of lung resulting in small hemithorax Local invasion of chest wall, ribs, heart, mediastinum, hilar nodes, and diaphragm; transdiaphrag matic spread and invasion of contralateral pleura Associated pleural plaques or interstitia l \201 brosis in a minority of cases. \200 \200 The role of MRI is unclear \200\224it may provide additional information in some cases, e.g . chest wall invasion, although is rarely required. PET may have a role in distinguishing b enign and malignant pleural disease as well as identi- fying lymph node spread for staging, although it is not widely used. 3. Biopsy The diagnosis should be con \201 rmed histologi cally except when the patient is too unwell or too frail for biopsy. Ultrasound- or CT-guid ed cutting needle biopsy and thoracoscopic biopsy of pleural masses have a high diagnostic yield and should be used in preference to blind (Abrams \200\231) biopsy techniques. Early use of thoracoscopy may both provide a diagnosis and enable treatment of large effusions wi th talc pleurodesis, thereby avoiding repeated non-diagnostic procedures with attendant pro blems of needle-track spread. Histological subtypes \200 Epithelioid (50% of cases; may be confused with adenocarcinoma; better prognosis) Sarcomato id (or \201 brous) Mixed (biphasic). \200 Immunohistochemistry is key to making the diagnosis. Positive staining for calretinin indic ates mesothelial origin (as opposed to adenocarcinoma), and staining for epithelial membran e antigen (EMA, also called CA15-3 and mucin-1) in a peripheral distribution strongly sugge sts mesothelioma. CEA staining is almost always negative in mesothelioma. Electron micros- copy of histopathological specimens may also help to distinguish mesothe- lioma from adenoc arcinoma. Staging No widely accepted staging system. Proposed schemes include Stage I \200 \223IV scheme and TNM classi \201 cation; surgery is required for \201 nal staging. Poor prognostic features include transdiaphragmatic muscle invasion and involvement of mediasti nal lymph nodes, male gender, poor performance status, and sarcomatoid histology. Further information BTS Statement on malignant mesothelioma in the United Kingdom. Thorax 2 007; 62: ii1 \200\223ii19. Robinson BW, Lake RA. Advances in malignant mesothelioma. NEJM 2005; 353: 1591 \200\2231603 . CHAPTER 17 Asbestos and the lung 116 Mesothelioma: treatment and outcome Treatment Management of pleural effusions Talc pleurode sis is the treatment of choice, and early pleurodesis is preferable to repeated pleural asp irations. This can be achieved either medically or at thoracoscopy, depending on local reso urces. Pleurodesis is not possible if the lung does not re-expand following drainage of ple ural \202 uid ( \200\230trapped lung \200\231), and the resulting recur- rent pleural eff usions are dif \201 cult to manage; indwelling pleural catheters allow \202 uid drainage without needle aspiration and are useful in this situa- tion. The value of pleuroperitonea l shunts remains uncertain. Radiotherapy Prophylactic radiotherapy appears to reduce chest wall invasion by tumor follo wing pleural aspiration or biopsy: three frac- tions reduced the risk of tracking from 40% to 0 in a randomized study of 40 patients, although a more recent study failed to demonstra te a bene \201 t. Recurrence may follow delayed prophylactic radiotherapy, so it is usuall y administered within 4 weeks. Palliative radiotherapy provides pain relief in a proportion of patients with chest wall pain, but is less useful in the treat- ment of breathlessness or SVCO. Surgery There are currently no reported randomized controlled trials assessing the outcomes of radical surgery, and its use is controversial. It should be considered only in centers with experience and if there is a \201 rm diagnosis of epithelioid mesothelioma, the pati ent is otherwise \201 t, and there is no radiological evidence of lymph node involvement. Avoid chemical pleurodesis in such cases. Operative mortality is approximately 6%. Trimoda lity therapy (extrapleuropneumonectomy followed by radio- therapy and chemotherapy) may hav e a role; trials are pending. Chemotherapy Patients with good performance status should have the option of discussing che motherapy with an appropriate specialist. Studies have suggested limited bene \201 ts with two different regimes. Pemetrexed (an inhibitor of certain DNA synthesis proteins, e.g. th ymidylate synthase) plus cisplatin has an objective response rate (tumor shrinkage of >50%) of 41% and appears to convey a survival advantage of just under 3 months when compared wit h cisplatin alone; pemetrexed has recently been approved by NICE, although it is expensive and ongoing treatment of an individual may be dependent upon objective metabolic responses based on CT-PET scanning. Gemcitabine plus cisplatin led to objective response rates of 33 and 48% in two trials, with quality-of-life bene \201 ts. Trials are ongoing.