CMV delivers a set tidal volume and respiratory rate, and is time-cycled. The tidal volume is usually delivered in the \201 rst part of the inspiratory phase, and is followed by th e inspiratory plateau before expiration begins. Peak inspiratory pressure depends on the in teraction of tidal volume, inspiratory \202 ow rate, airway resistance, and lung complian ce. Plateau pressure is an indicator of the pressure transmitted to the alveoli, and is an important determinant of ventilator-induced lung injury (VILI). CMV does not allow spontane ous breaths, and is approp- riate for patients who have no respiratory effort. If the patie nt coughs or tries to take a breath, high airway pressures and work of breathing may be gen erated. \200 Pressure controlled ventilation (PCV) delivers a set air- way pressure and r espiratory rate, and is time-cycled. Tidal volume depends upon the inspiratory pressure, in spiratory time, airway resistance and lung compliance. PCV does not permit spontaneous resp iration. The risk of high airway pressure is avoided, but tidal volumes and minute ventilat ion are variable. Tracheostomy Until the mid-1980s, tracheostomy was almost exclusively performed as an open, surgical procedure. Since that time several percutaneous techniques have been described wh ich can be performed at the bedside in the ICU. The most pop- ular is that described by Cia glia, using a seldinger guidewire and either serial dilators or a single tapered dilator. \200 The most common indication for tracheostomy in the ICU is to aid weaning from respira tory support in patients who need ventilation for more than a few days. Other indications i nclude upper airway obstruction and impaired bulbar function. A mini-tracheostomy may help in the management of secretions in self-ventilating patients with an inadequate cough. The major bene \201 t is improved comfort (compared to an oral ETT), allowing sedation to be stopped. Airway resistance and anatomical dead space are reduced, and easier mouth care may reduce the risk of VAP. Assist-control ventilation (ACV) delivers a set tidal vol- ume. Each breath is triggered by the patient \200\231s inspiratory effort (assist). If the patient does not trigger the ven tila- tor, the set tidal volume is delivered at a set back-up respiratory rate (control). A CV is the mode of ventila- tion employed in the ARDS Network studies. Risks of tracheostomy include hypoxaemia, bleeding, infection, and damage to the trachea or esophagus. Severe hypoxia may be due to loss of airway control at the time of tracheostomy formation, or dislodgement or obstruction of the tube at a later time. To reduce the risk of blockage, a tracheostomy tube may have an inner lining tube which can be removed and cle aned. Bleed- ing may occur at the time of the procedure or due to erosion through an adjace nt vessel days or weeks later. Infection is usually not severe but mediastinitis, especiall y in the presence of a median sternotomy wound, may be catastrophic. The risk of infection is less with percutane- ous tracheostomy than with open tracheostomy, proba- bly due to the difference in the amount of tissue trauma. \200 Contra-indications to tracheostomy inclu de soft tissue infection of the neck, and signi \201 cant thrombocytopenia or coagulopathy . Patients with abnormal neck anatomy such as a goiter or a pulsatile vessel above the ster nal Synchronized intermittent mandatory ventilation (SIMV) enables a set number of ventilator b reaths (either volume controlled or pressure controlled) to be syn- chronised with the pati ent \200\231s spontaneous respiratory efforts. Patients can also breathe between these mand a- tory breaths, with pressure support added to the extra breaths. Patient-ventilator dyssy nchrony may still occur, with increased work of breathing. Biphasic positive airway pressure (BIPAP) alternates between two levels of airway pressure, providing tidal ventilation but permitting spontaneous breaths through- out the ventilator cycle. Spontaneous breaths can be CHAPTER 17.6 The ventilated patient 437 augmented by pressure support. Like SIMV, BIPAP can provide complete or partial ventilatory support, but the ability to take a spontaneous breath at any time renders it better tolera ted than SIMV. Extra-corporeal membrane oxygenation (ECMO) achieves gas exchange via an extra-corporeal circuit similar to that used for cardio -pulmonary bypass during surgery. It is used as a rescue therapy in patients with severe, r efractory hypoxia. There is currently no good evi- dence of bene \201 t in adults, but the results of the CESAR trial in patients with severe ARDS are awaited. Pressure support ventilation (PSV). The patient trig- gers each breath. The ventilator deli vers a set level of inspiratory pressure, and cycles to expiration when the inspiratory \202 ow rate drops below a certain level. Tidal volume depends upon the interaction between inspiratory pressure, inspiratory time, airway resistance and lung compliance. PSV is used for weaning patients from respiratory support, once they have recovered from the acute pha se of critical illness. A mandatory mode of ventilation acts as a back up, activated by apn oea. Ventilator settings It is important to understand the various modes of ventila- tion, but c urrent evidence suggests that other ventilator settings such as tidal volume and airway pre ssure have more in \202 uence on outcome: \200 FiO2 should start at 0.6 \200\2231.0, and be titrated according to PaO2 (aiming for 8 \200\22310kPa) and SpO2 (aiming for at least 9 0 \200\22395%). Until the patient has been stabilized, the over-riding concern is to avoid hypoxaemia. In patients with severe chronic respiratory failure or severe ARDS, a lower PaO 2 or SpO2 may be accepted, as long as tissue oxygenation appears to be adequate, as assesse d by end-organ function, central venous oxygen satura- tion, lactate and base de \201 cit. The duration and severity of an SpO2 less than 90% is correlated with cognitive impairment in survivors of severe ARDS. The effect of oxygen therapy on the hypoxic respiratory drive is ir- relevant in the mechanically ventilated patient in the acute setting. However, it m ay become important dur- ing weaning. Hyperoxia is bene \201 cial in the treatment of carb on monoxide poisoning but should be avoided in other circumstances. Oxygen toxicity occurs after 12 \200\22336 hours at an FiO2 above 0.5, and is characterized by lung in \202 ammat ion and atelectasis, the clinical importance of which is not clear. Triggering is the mechanism by which the ventilator recognizes a patient \200\231s attempt to take a spontaneous breath. The ventilator measures either a small negative de \202 ecti on in airway pressure, or a change in the rate of air \202 ow within the breathing system . Modern ICU venti- lators measure changes in both pressure and \202 ow. Flow can be meas ured earlier, and provides a more sensitive trigger which reduces work of breathing. Positive end-expiratory pressure (PEEP) occurs when airway pressure remains above atmospher ic pressure at the end of expiration. It may be set externally by the ventilator, or may be intrinsic (PEEPi) when there is increased resistance to expiratory \202 ow in the airway s, as in asthma or COPD. PEEP is used therapeutically to recruit collapsed areas of lung, i ncrease FRC, and improve ventilation-perfusion matching, leading to better arterial oxygena tion. There is less cyclical opening and closing of small airways with each breath, reduc- ing shear forces and lung injury ( \200\230open lung ventilation \200\231). Tidal ventilati on occurs on the steeper part of the pres- sure-volume curve, with improved lung compliance and reduced work of breathing. Excessive PEEP may cause barotrauma, increase pulmonary vas cular resistance and paradoxically worsen shunt by diverting blood \202 ow away from over -distended lung units. \200\230Best PEEP \200\231 is de \201 ned by the minimum level whi ch achieves an acceptable PaO2. Different levels of PEEP did not affect mortality in ARDS p atients receiving carefully controlled tidal volumes and inspiratory pressures. Respiratory rate is typically 12 \200\22316 breaths per minute, adjusted with the tidal vol ume in order to achieve an acceptable CO2 clearance and arterial pH. In severe asthma or CO PD a slower rate (8 \200\22310 breaths per minute) may be necessary. This allows suf \201 cient time for inspira- tion without excessive peak airway pressures, and for full expirati on without dynamic hyperin \202 ation. Tidal volume used to be set routinely at 10 \200\22312ml/kg. However, there is evidence tha t in patients with ARDS these tidal volumes contribute to ventilator-induced lung injury an d increase mortality. A target of 6ml/kg in patients with ARDS is appropriate, based on bod y weight predicted from height and sex. In other ICU patients the evidence is less clear, b ut it is prudent to limit tidal volume in all patients where possible. Continuous positive airway pressure (CPAP) is delivered by a ventilator or by speci \201 c CPAP equipment. It gives no support for tidal ventilation but, like PEEP, it improves lung compliance and oxygenation. It is useful to reduce work of breathing and maintain FRC duri ng the \201 nal stages of weaning from ventilation. Inspiratory pressure should be set to achieve the desired tidal volume and minute ventilati on, while keeping the plateau pressure below 30cmH2O. Once again the evi- dence for this co mes from trials in patients with ARDS, and its applicability to other populations is uncert ain. \200 Inspiratory: expiratory ratio is normally 1:2. A ratio approaching 1:1 or inver se ratio ventilation (2:1) increases mean airway pressure, recruits alveoli, allows more ev en distribution of ventilation and improves V/Q matching. It is used as part of a strategy to manage severe hypoxaemia. Ensure that there is enough time for full expiration, by obser ving the expiratory \202 ow waveform return to zero between breaths. Prolonged expiration with a ratio of 1:3 or 1:4 may be necessary in COPD or asthma. Prone ventilation may be used in patients with refrac- tory hypoxia, and improves oxygenati on in about 60% of patients with ARDS. However, it may cause haemodynamic instability and a irway compromise, and has not been shown to reduce mortality or duration of ventilation. High frequency oscillatory ventilation (HFOV) typically delivers 180 \200\223360 breaths pe r minute, the tidal volume being smaller than the anatomical dead space. The mechanism of g as exchange is not completely under- stood, but both oxygenation and CO2 removal may be imp roved. Randomized trials in adults with ARDS have revealed no signi \201 cant bene \201 t s over conventional ven- tilation for either mortality or duration of ventilation. HFOV may be used as a rescue therapy in patients with ARDS or a broncho-pleural \201 stula when c onventional ventilation is failing. PEEP may be set at 5 cmH2O in ventilated patients with relatively normal lungs requiring an FiO2 of up to 0.4, in order to prevent atelectasis. In patients requiring a higher FiO2, P EEP may be increased up to 10 \200\22315cmH2O T PALFREYMAN & T EVANS 438 on a sliding scale as the FiO2 also increases towards 1.0. The ARDS Network trials used a s liding scale of PEEP up to a maximum of 24cmH2O. However, such high PEEP is rarely used in practice. An alternative method of setting PEEP is to look at the pressure-volume curve and adjust PEEP so that tidal ventilation takes place on the steep part of the curve. In patie nts with expiratory air \202 ow limitation the external PEEP should be set just below int rinsic levels (PEEPi) in order to reduce the work of breathing required to trigger a pressu re sup- ported breath. with other haemodynamic data, clinical examination and the CXR. However, there are no studi es to show that measuring the EVLW by single thermodilution reduces either mortality or dur ation of ventilation. Clinical examination is limited by the patient \200\231s recumbent position and their inabi lity to perform the usual manoeu- vres required for full assessment. However, within these limits, thorough clinical examination is essential in order to put the monitored data in co ntext and to pick up prob- lems which would not otherwise be apparent. Inadequate clinical examination may lead to missed or delayed diag- noses which a critically ill patient will t olerate poorly. Lung-protective ventilation is the ventilator strategy used in ARDS to minimize VILI. It in cludes limitation of tidal volume (6ml/kg) and plateau pressure (30cmH2O), and use of PEEP for open lung ventilation. Weaning from invasive ventilation Weaning is the process of withdrawing ventilatory support until the patient breathes unaided. In 80% of patients this is achieved quickly and easily once the original reason for ventilation has resolved, but in 20% of patients it may take prolonged efforts over several days or weeks. \200 Patients should be screened every day for readiness to wean, looking for: resolution of the problem which required ventilation; h aemodynamic stability; adequate gas exchange; absence of serious acid-base or electro- lyte abnormalities, and an alert cooperative patient. Many physiological parameters have been s tudied in attempts to predict readiness to wean, but none have been found to be consistentl y accurate. Permissive hypercapnia may be necessary in ARDS or in other patients who are dif \201 cult to ventilate such as those with severe asthma or persistent pleural air leaks. The PaCO2 i s allowed to rise to 8 \200\22310kPa in order to limit tidal volume and airway pressure. Ho wever, arterial pH should be maintained above 7.2 \200\2237.25 by limiting the rise in PaCO 2. Monitoring the ventilated patient \200 Routine monitoring includes continuous pulse oxime try, ECG and invasive arterial pressure measurement. Arterial blood gas (ABG) analysis should be performed 15 \200\22330 minutes after adjusting the ventilator, and 1 \200\2234 hourly depending on the severity of illness and the need f or other measurements such as blood glucose. Having ful \201 lled the screening criteria, a patient should undergo a spontaneous breath ing trial (SBT) for 30 \200\223120 minutes, using a low level of PSV, CPAP or a T-piece. Su ccess is indicated by comfortable breathing at a rate <35/min, adequate gas exchange, and c ardiovascular stability at the end of the trial. Important ventilator measurements include inspiratory and expiratory tidal volume, airway p ressures, inspira- tory and expiratory \202 ow rate, respiratory rate and FiO2. Observati on of the expiratory \202 ow curve is a useful way to ensure that intrinsic PEEP is minim ized and that breaths are not being \200\230stacked \200\231 leading to hyperin \202 atio n. \200 End-tidal CO2 (ETCO2) may correlate poorly with the PaCO2 in ICU patients due to V/Q mismatch and shunt, and is not routinely monitored. However, it is essential for con \201 rmation of tracheal placement of the ETT at the time of intubation. It may also be use d continuously in patients with raised intracranial pressure, for whom tight control of the PaCO2 is necessary. If a patient fails the SBT, they are returned to supported ventilation. Weaning may then pr ogress by repeated breathing trials, or by incremental reduction of PSV over the following days. The level of support may be varied during the day in order to exercise the respirator y muscles. In patients with COPD or cardiogenic pulmo- nary oedema, weaning may be expedite d by extubation directly onto NIV. After short-term ventilation with rapid weaning, the ar- ti \201 cial airway is usually re moved immediately. The risk of reintubation within 48 hours is about 13%. After pro- longed weaning, removal of a tracheostomy is usually delayed for 24 hours in case respiratory fai lure recurs. After successful weaning, an arti \201 cial airway may still be needed in som e patients to prevent airway obstruction, to enable suctioning or prevent aspiration. Alarms on the ventilator and monitor should be set to provide adequate warning of deteriora tion, and to minimize false alarms caused by minor changes. Alarms should not simply be dis abled in order to reduce noise. \200 Plain CXR should be performed when clinically indica t- ed, rather than as part of the daily routine for every ICU patient. Routine CXR is not a ssociated with an improve- ment in ICU or hospital length-of-stay or in-hospital mortality. Targeted CXR is a useful investigation in the ICU, but almost all \201 lms are taken in recumbent patients and may not reveal clinically signi \201 cant pleural effusions or pneu mothoraces. When the lungs are very stiff, even a small pneumothorax may be under tension a nd may cause haemodynamic instability. Ultrasound scanning or CT should be considered when the CXR is equivocal. Weaning protocols have been shown to reduce the duration of ventilation and ICU length of s tay in some studies, but other studies have found no difference. Protocols may be less impo rtant in intensivist managed ICUs which have high levels of physician staf \201 ng and str uctured ward rounds. General care of the ventilated patient General care of the ventilated patient includes adeq uate sedation and analgesia, preventive measures against deep vein thrombosis and gastric s tress ulceration, nutrition, meticulous infection control and one-to-one nursing care. Rais ing the head of the bed by 45 above horizontal has been shown to signi \201 cantly reduc e the incidence of VAP. Extra-vascular lung water (EVLW) is a variable derived from the thermodilution curve of som e cardiac output monitors. It provides an estimate of lung oedema, and may help to guide \202 uid balance management in conjunction CHAPTER 17.6 The ventilated patient 439 Further reading Drakulovic MB, Torres A, Bauer TT et al. Supine body position as a risk fac tor for nosocomial pneumonia in mechanically ventilated patients: a randomized trial. Lance t 1999; 354: 1851 \200\2231858. Kahn JM, Goss CH, Heagerty PJ et al. Hospital volume and the out- comes of mechanical venti lation. N Engl J Med 2006; 355: 41 \200\22350. Kripoval M, Shlobin OA, Schwartzstein RM. Ut ility of daily routine portable chest radiographs in mechanically ventilated patients in th e medical ICU. Chest 2003; 123: 1607 \200\2231614. Esteban A, Anzueto A, Frutos F, et al. Characteristics and outcomes in adult patients recei ving mechanical ventilation. JAMA 2002; 287: 345 \200\223355. Krishnan JA, Moore D, Robeson C et al. A prospective controlled trial of a protocol-based s trategy to discontinue mechanical ven- tilation. Am J Respir Crit Care Med 2004, 169: 673 \200\2238. Esteban A, Alia A, Tobin MJ, et al: Effect of spontaneous breathing trial duration on outco me of attempts to discontinue mechanical ventilation. Am J Respir Crit Care Med 1999; 159: 512 \200\223518. Meade M, Guyatt G, Cook D, et al. Predicting successful weaning from mechanical ventilation. Chest 2001; 120: S400 \200\223404. Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of sever e sepsis and septic shock. N Engl J Med 2001; 345: 1368 \200\2231377. Esteban A, Frutos-Vivar F, Ferguson N, et al. Noninvasive positive pressure ventilation for respiratory failure after extubation. N Engl J Med 2004; 350: 2452 \200\2232460. The ARDS Network. Ventilation with lower tidal volumes as compared with traditional tidal v olumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 2000 ; 342: 1301 \200\2231308. Ferrer M, Esquinas A, Arancibia F, et al. Non-invasive ventilation during persistent weanin g failure: a randomized controlled trial. Am J Respir Crit Care Med 2003; 168: 70 \200\2237 6. Guerin C, Gaillard S, Lemasson S, et al. Effects of systematic prone positioning in hypoxem ic acute respiratory failure, a randomized controlled trial. JAMA 2004; 292: 2379 \200\2232 387. The ARDS Network. Higher versus lower positive end-expiratory pressures in patients with th e acute respiratory distress syn- drome. N Engl J Med 2004; 351: 327 \200\22336. Henderson JJ, Popat MT, Latto IP, Pearce AC. Dif \201 cult airway society guidelines for m anagement of the unanticipated difficult intubation. Anesthesia 2004; 59: 675 \200\223694. Withholding and withdrawing life-prolonging treatments: Good practice in decision-making. General Medical Council, London 2002. This page intentionally left blank 441 Chapter 18 Orphan lung diseases/BOLD Chapter contents 18.1 Pulmonary alveolar proteinosis 442 18.2 Churg \200\223Strauss syndrome 446 18.3 Ciliar y dyskinesia 448 18.4 Pulmonary Langerhans \200\231 cell histiocytosis 450 18.5 Lymphangiol eiomyomatosis 452 18.6 Primary tracheal tumors 454 18.7 Pulmonary arteriovenous malformatio ns 456 18.8 Pulmonary amyloidosis 458 C MORGAN 442 18.1 Pulmonary alveolar proteinosis Pulmonary alveolar proteinosis (PAP) is extremely rare (prevalence around 0.2 per million) but nevertheless impor- tant because when optimally managed it should generally have a good prognosis, but ignored or poorly managed may well lead to preventable death. There have be en important developments in the understanding of the pathogenesis and following this, the treatment of PAP in the last decade. This is all the more remarkable considering the rarity of PAP and the fact that it was only \201 rst described as a clinical entity in 1958. In deed, unraveling the mystery of this enigmatic syn- drome may shed important light on the p athophysiology and cell biology of more common diseases. One-third of patients suffer very severe symptoms and extreme limitation of function, progr ess despite treat- ment and die of chronic hypoxaemia, cor pulmonale or superseding infecti on. While the \200\230rule of thirds \200\231 is undoubtedly an oversimpli \201 ca- tion, it nevertheless stands as a guide to prognosis. Etiology and pathophysiology The key appears to be the function of the alveolar macro- phag e (AM) which has a central role in both surfactant turnover and in pulmonary host defense, both of which are disordered in PAP. The AM migrates to the pulmonary interstitium and then matures to full functional capacity under the in \202 uence of granulocyte monocyte colon y stim- ulating factor (GMCSF). In the absence of proper function of the AM there is a prog ressive build up of effete sur- factant lipoproteins within the alveolar space together wit h other debris such as foamy and immature AMs. This reduces lung volumes, prevents effectiv e gas exchange across the alveolar-capillary membrane and causes the typical hypxaemia. In the congenital form of PAP there is a fundamental (and fatal) failure of GMCSF receptor sen siti- vity but in the cases of primary PAP there is an IgG auto- antibody to circulating GM CSF so that GMCSF expression is neutralized. This is similar to a mouse model where geneti- cally modi \201 ed (gene knock-out) homozygotes incapable of expressing GMCSF develop a p ulmonary syndrome identical to PAP. It is not possible to explain all cases of secondary PA P along similar lines but is intriguing that the vast majority of cases of secondary PAP ar e secondary to a haematologi- cal malignancy, implying that there may be some as yet unex- plained acquired defect of GMCSF sensitivity. Epidemiology There are 3 distinct forms of PAP which share practically identical clinical f eatures but have very different triggers or etiology. These forms are \200 Congenital (extremely rare and least amenable to treat- ment \200\223 almost universally f atal in early infancy). Unlikely to present to many clinicians because of rarity and absenc e of therapeutic options. Secondary (PAP in association with or caused by a range of severe clinical entities such as hematological malig- nancy, lung cancer, infection, massive expo sure to inhaled irritants such as gasoline fumes or silica dust). The outcome is generally dependant entirely on the management of the precipitating condition, for example, control o f the leukemia may lead to remission of the secondary PAP. Primary (previously referred to as idiopathic, now increasingly referred to as auto-immune). This is the most common form a t around 0.2 per million and the form that requires speci \201 c management. It is primary PAP that is best studied and understood and accounts for more than 90% of cas es of PAP. Most reported series show an average age at onset in the late 30s but all ages c an be affected with a 5 to 1 male predominance. There is no apparent ethnic propensity othe r than PAP being more common in Japan where \201 rst presentation is typically at an olde r (late 50s) stage. Diagnosis (and differential diagnosis) The diagnosis is in two parts, one to con \201 rm t he clinical fea- tures of PAP and two, to look for evidence for provocative processes assoc iated with secondary PAP. The typical gradual onset of exercise intolerance and dyspnoea in the absence of features of heart disease or serious pulmonary disease is sug- gestive. The plain chest radiograph typically reveals diffuse bilateral airspace shadowing and the abse nce of features of cardiac disease or lymphadenopathy is important. Clinical presentation In most cases there is an insidious progressive decline in exercise t olerance and increasing dyspnoea. Some patients have a non-productive cough and some report various types of chest pain (neither pleuritic nor anginal in nature) while some patients present with combinations of the above. In some cases there is an apparently acute onset wi th features of respiratory infection, fever and even sweats. It is possible that this may b e the true onset of acute PAP but more likely that an infection (PAP patients prone to oppo rtunistic and conventional infection) exacer- bates the insidious decline. There may be cen tral cyanosis which worsens on activity and measured pulse oximetry may show SpO2 in the lo w 90s falling to the 80s on exer- cise or stress. Finger clubbing is rare but reported. A v ery small minority of PAP patients present with relatively rapid onset respiratory failure. Since the earliest published reports of PAP there has been an apparent \200\230rule of th irds \200\231: \200 One-third of patients have very mild disease which has only a small i mpact on their health, may not progress and may even get spontaneously better One-third of patients have moderate to severe disease which has a signi \201 cant impact and may progre ss and require a series of treatment options (see later) Fig. 18.1.1 CXR of PAP. CHAPTER 18.1 Pulmonary alveolar proteinosis 443 Pulmonary function studies often con \201 rm a restrictive lung defect with reduced lung v olumes and impaired gas trans- fer. Routine blood tests are generally normal apart from ele vated lactate dehydrogenase (LDH). In fact the elevated LDH is a fairly consistent feature and may even be a useful proxy for adequacy of control of the PAP. Unfortunately many clini cal biochemistry laboratories now omit LDH from the standard panel of \200\230liver functi on tests \200\231 and LDH is obsolete as a \200\230cardiac enzyme \200\231 so it needs to be speci \201 cally requested as a marker of PAP. The typical sequence of events is that t he patient presents, initial investigations are inconclusive for anything, a course of anti biotics is con- sumed with no improvement and the chest radiograph which is still abnormal leads on to referral to pulmonary specialist, then high resolution CT scan of the thorax, \201 bre-optic bronchoscopy (FOB) and diagnostic broncho- alveolar lavage (BAL) which is i deal because this sequence will unequivocally seal the diagnosis in the majority of cases. Fig. 18.1.3 Pathology PAS stain of alveoli \201 lled with lipo-protein. (see Plate 15.) The differential diagnosis includes a text book full of poten- tial causes of dyspnoea, res trictive pulmonary defect and diffuse pulmonary in \201 ltrates but the strikingly individ ual features of PAP, despite its extreme rarity usually makes the elimination of alternativ es relatively easy. Treatment Treatment options include: \200 \200 Observation. Lung lavage: \200 \200 GMCSF-related: \200 \200 Immunotherapy: \200 \200 Segmental therapeutic lavage during FOB. Whole lung lavage. Exogenous GMCSF by injection. Exogenous GMCSF by aerosol inhalation. Anti-B lymphocyte \200\223 using rituximab. Plasmapheresis. Fig. 18.1.2 Chest CT of PAP. In patients who are stable, with only mild physiological impairment compatible with their p ersonal needs and daily activities, it is reasonable to observe for a while because some pa tients in this group enjoy spontaneous remission. Where symptoms are more signi \201 cant and interfere with normal life and work, treatment should be offered. Repeated segmental th erapeutic lavage via FOB has been used and can be effective but most patients prefer the gr eater potency of whole lung lavage (WLL) under general anesthesia. This is a specialist pro cedure and should be con \201 ned to a small number of dedicated units worldwide. The safe ty and ef \201 cacy depends on the absolute perfect placement of a double-lumen endobronch ial tube to sepa- rate left and right lungs so that one lung can be adequately ventilated w ith 100% oxygen (because of the exacerbation of the resting hypoxaemia by single-lung venti lation) while the other is \201 lled and indeed \200\230ventilated \200\231 with saline until all the lipoproteinaceous material is lavaged out and subse- quent ef \202 uent is c lear. This may take 40 or more litres and more than 3 hours. Some of the saline remains in the lung despite attempts at complete drainage so it is essen- tial the patient is kept asl eep and ventilated for several hours after the procedure during which time all residual sal ine is absorbed and the full bene \201 ts of the \200\230washed-out \200\231 lung start t o manifest. In some cases both lungs are lavaged in sequence. In most cases the WLL has to be repeated several times before satisfactory and prolonged remission is achieved. There ar e well documented data showing improvement in pulmonary function, resting SpO2, exercise The CT is almost pathognemonic because the features of \200\230crazy paving \200\231, geog raphic distribution of airspace shadow- ing and ground glass opacities and the absence of o ther features (mediastinal lymphadenopathy, pulmonary \201 bro- sis, cardiac anomalies et c.) are speci \201 c for PAP. The extent of PAP features on the CT may be a useful guide t o the likely progression or response to therapy. The FOB should reveal normal airways but t he BAL is very striking. The saline goes in clear but comes back laden with lipoproteins an d macrophages and looks like a milky, yellowish, opales- cent colloid which is unique to PA P. Light microscopy of the BAL reveals typical features of periodic acid \200\223Schiff (PA S) staining material with cholesterol clefts and abun- dant macrophages. The BAL should be sent for microbio- logical analysis because there is a well-reported tendency to opportunis tic infection in PAP, typically with pneumo- cystis, nocardia and mycobacterium (including atypical mycombacteria). Only rarely should it be necessary to resort to open lung biopsy t o con \201 rm the diagnosis of PAP if the other elements are typical. The next question is to differentiate between forms of PAP. Features suggestive of any of the serious condition s associated with secondary PAP should be carefully excluded. The presence of high titres o f the anti-GMCSF antibody and the absence of any suggestion of a secondary etiology con \201 rms primary PAP. This distinction is important in terms of planning and assessing subs equent therapy. C MORGAN 444 tolerance and imaging after WLL. Symptoms such as dysp- noea and even cough and chest pain can be relieved by a successful program of WLL. Most importantly the patient feels better. Though invasive, the procedure is inherently safe provided it is undertaken appropriately a nd the airway management is secure. Consider rituximab or other options if the above does not produce remission. Keep all patie nts under review until long established remission is obtained. Other things to consider: \200 The psychological impact of prolonged chronic dysp- noea and repeated hospital episodes. Th e ever present risk of infection of lung and other sites with conventional and unconvention al opportunistic organisms. The principles of rare disease management \200\223 the need fo r concentration of effort and increase in knowledge. Alternative treatments A minority of patients either fail to respond to WLL or they re-accu mulate alveolar material so quickly that the WLL has to be repeated at excessively short in tervals (e.g. less than 1 month). Then alternative options should be considered. The option with by far the most experience so far is the use of exogenous GMCSF. It may seem odd tryi ng to treat an auto-immune disorder with the target of the auto-immunity but John Seymour i n Melbourne treated several PAP patients with daily sub-cutaneous GMCSF injections successf ully before the existence of the anti- GMCSF antibody was appreciated. Around half of that series of patients obtained remission and the non-responders suffered no obvious harm. Many more patients have subse- quently demonstrated a similar response rate and absence of seri ous side effects. The drug is very expensive however, and there have been great dif \201 c ulties with reliable supply because of pharmaceutical issues. An alternative approach, to s ave money and to deliver the drug to its actual site of action is to use the aerosol inhala tion route and there have been very promising results from this approach (11 out of 12 pati ents in Mayo Clinic study). There have been anecdotal reports of use of plasmapher- sis to remove the causative antibody or to switch off its production using the selective agent rit uximab but much less experience than for WLL and GMCSF. The ideal management of PAP: \200 Con \201 rm the diagnosis of PAP. \200 Look for and rule out differential diagnoses or condi- tions which cause secondary PAP or aggravate primary PAP. Confirm the presence of th e anti-GMCSF antibody (requires assay at specialist center). Treat \200\223 WLL \201 rst then move on to aerosol inhaled GMCSF in patients who do not remit after 6 episodes of WLL . Further reading Beccaria M, Luisetti M, Rodi G, et al. Long-term durable bene \201 t after whole lung lavage in pulmonary alveolar proteinosis. Eur Respir J 2004; 23: 526 \200\22353 1. Characteristic pulmonary pathology. Proc. Natl. Acad Sci 1994; 91:5592 \200\2235596. Kitamura T, Tanaka N, Watanabe J, et al. Idiopathic pulmonary alveo- lar proteinosis as an autoimmune disease with neutralizing anti- body against granulocyte-macrophage colony stimu lating factor. J Exp Med 1999; 190:875 \200\223880. Ramirez RJ, Schult RB, Dutton RE. Pulmonary alveolar proteinosis: a new technique and ratio nale for treatment. Arch Intern Med 1963; 112:419 \200\223431. Rosen SH, Castleman B, Liebow AA. Pulmonary Alveolar Proteinosis. N Engl J Med 1958; 258:1123 \200\2231142. Seymour JF, Dunn AR, Vincent JM, et al. Ef \201 cacy of granulocyte- macrophage colony-sti mulating factor in acquired alveolar proteinosis. N Engl J Med 1996; 335: 1924 \200\2231925 . Seymour JF, Presneill JJ. Pulmonary alveolar proteinosis: progress in the \201 rst 44 yea rs. Am J Respir Crit Care Med 2002; 166: 215 \200\223235. Stanley E, Lieschke GJ, Grail D, et al. Granulocyte/macrophage colony-stimulating factor-de \201 cient mice show no major p ertur- bation of hematopoiesis but develop a characteristic paulmonary pathology. Proc Natl Acad Sci USA 1994; 91: 5592 \200\2235596. Trapnell BC, Whitsett JA, Nakata K. Pulmonary alveolar proteinosis. N Eng J Med 2003; 349: 2527 \200\2232539. Wylam ME, Ten R, Prakash UBS, et al. Aerosol granulocyte- macrophage colony-stimulating fac tor for pulmonary alveolar proteinosis. Eur Respir J 2006; 27: 585 \200\223593. This page intentionally left blank T MAHER & D GEDDES 446 18.2 Churg \200\223Strauss syndrome Churg \200\223Strauss syndrome is a multi-system disorder that typically occurs in severe a sthmatics. It is characterized pathologically by granulomata and necrotising eosi- nophilic vasculitis. Estimated annual incidence is 2.4 \200\2236.8 per million. Mean age of onset i s 48 years. Males and females are equally affected. Etiology is poorly understood; key fact ors in the devel- opment of Churg \200\223Strauss syndrome appear to be atopy and asthma, a nti-MPO (myeloperoxidase) autoantibod- ies and the toxic effects on tissues of activated eo si- nophils. Leukotriene antagonists have been linked to over 160 cases of Churg \200\223St rauss syndrome. It is postulated that this is due to a tapering of corticosteroid dosage in patients with hitherto unsuspected Churg \200\223Strauss syn- drome rather than direct dru g toxicity. Cardiac: this occurs in 40% of patients and is associated with signi \201 cant mortality. May present as: eosinophilic endomyocarditis, coronary vasculitis, valvular dysfunc- tion, or pericarditis. Cardiac failure is the commonest presentation. Gastrointestinal: abdominal pain, diarrhea, and or bleeding occurs in up to 60% of patients. Histological changes can occur throughout the GI tract but are most common in the small intestine and colon. Bowel p erfora- tion is the most serious pcomplication. Renal glomerulonephritis is common, renal f ailure how- ever, is rare Cutaneous may include: erythema, pustules, vesicles, ulcers, skin nodules or palpable purpura. Examination Examination \201 ndings are dictated by pattern of organ involvement. The foc us of examination in the patient with suspected Churg \200\223Strauss syndrome should be: ( 1) con- \201 rming the diagnosis; (2) identifying sites for biopsy and (3) characterizing the extent of organ involvement. Disease classi \201 cation Individuals with Churg \200\223Strauss syndrome may manifest a spectrum of abnormalities that frequently make the diag- nosis a challenging one to con \201 rm. A number of classi \201 ca- tion schemes have been developed in an attempt to sys tematize the diagnosis of this condition. The American College of Rheumatology classi \201 cation criteria (Table 18. 2. 1) are the most applicable in the clinical setting. Investigation As with examination, investigations should be aimed at con \201 rming diagno sis and assessing the pattern and extent of organ involvement. Laboratory \200 Table 18.2.1 American college of rheumatology classi \201 cation scheme for Churg \200\223 Strauss syndrome FBC characteristically shows a marked eosinophilia (>1500 cells/ L). This may \202 uctua te and is often masked by corticosteroids. ANCA (anti-neutrophil cytoplasmic antibodies) is posi- tive in a peri-nuclear pattern in half of patients with Churg \200\223Strauss syndro me. This should be con \201 rmed by demonstration of anti-MPO antibodies. In \202 ammator y markers (ESR, CRP) will be raised in active disease and provide a useful measure of respo nse to therapy. Diagnosis of Churg \200\223Strauss syndrome is likely when at least four criteria are prese nt (sensitivity 85%, speci \201 city 99.7%) (1) Asthma (2) Blood eosinophilia >10% (3) Neuropathy (mononeuropathy or polyneuropathy) (4) Pulmonary in \201 ltrates (5) Paranasal sinus abnormality