Polymeric Z AAT is chemotactic for human neutrophils. This proin \202 ammatory effect of p olymers may explain the progression of lung disease and airway obstruction after smoking ce ssation in PI*Z individuals. Zantitrypsin Panniculitis that is characterized by painful red nodules on the thighs or buttocks. It res ults from uncontrolled proteolysis within the skin. Oxidation Polymerisation Plasma deficiency Reduced inhibitory activity ANCA positive systemic vasculitis and Wegener \200\231s granu- lomatosis are rare complications. Nephropathy with membranoproliferative glomerulone- phritis especially in children and youn g adults. This may be a consequence of the associated liver disease. Inactivation Pro-inflammatory Investigations PI*Z AAT de \201 ciency is suspected where plasma AAT levels are abnormally low (< 0.5g/l) in individuals with associated diseases. The diagnosis is con \201 rmed by identifying abnor- mal AAT phenotypes by isoelectric focusing. Genotyping offers diagnosis at the molecular level. EMPHYSEMA Fig. 5.8.1 Mechanisms for the pathogenesis of emphysema. CHAPTER 5.8 Alpha-1-antitrypsin de \201 ciency 121 (a) Fig. 5.8.2a Mutants of AAT (left) cause the protein to link together as dimers (middle) tha t extend to form chains of polymers that are retained within hepatocytes. Fig. 5.8.3 Emphysema with basal radiolucency. Lung function tests \200 Spirometry, static lung volumes, ABG analysis and gas transfer s hould be measured at baseline and generally mirror abnormalities seen in \200\230usual \200\231 COPD except in being out of proportion to the smoking history. \200 FEV1 is the most important predictor of survival. \200 There is a wide variation in bronchodilator re sponse which may explain why some cases of AAT-de \201 cient COPD are diagnosed as asthma. (b) Fig. 5.8.2b Polymers of Z AAT that are retained within hepatocytes. Some individuals have discordant physiology with marked emphysema and little airway disease or vise versa for reasons that remain unclear. Natural history Liver dysfunction represents the major clinical problem before the third de cade while lung function is preserved. Lung dysfunction begins thereafter. A more rapid rat e of FEV1 decline is associated with: \200 male sex; \200 age between 30 to 44 years; \200 current smoking; \200 FEV1 between 35 \200\22360% predicted; \200 bronchodilator response (asthmatic features); \200 chronic bronchitis; \200 previous episodes of pneum onia. Severe AAT de \201 ciency is associated with shortened life expectancy and survival falls exponentially as FEV1 declines to <35% predicted. Median life expectancy for smokers is between 40 \200\22349 years and 65 \200\22369 years for never smokers. Emphysema and cir rhosis are the most common causes of death (72% and 10% respectively) and account for the e xcess mortality. (c) Fig. 5.8.2c The accumalation of Z AAT causes cirhosis (left) and cherry red PAS positive in clusions (right). Radiology \200 The CXR is normal in early disease. Hyperin \202 ation, dia- phragmatic \202 attening and increased lower lung radiolu- cency may be evident in advanced disease ( Fig. 5.8.3). \200 HRCT is more sensitive for detecting emphysema in AAT de \201 ciency. It allows assessment of the severity of associated bullous disease and bronchiectasis. AUTHOR \200\231S TIP Cirrhosis in adults is more commonly the underlying cause of death in non smokers which is consistent with cirrhosis affecting survivors over the age of 50 years . U EKEOWA & D LOMAS 122 Management and treatment Preventing the development of COPD is solely depend- ent on early smoking cessation and limiting exposure to environmental pollutants. The prevalence of smok ing in PI*Z adolescents who are aware of their diagnosis is half that of age-matched peers. Guidelines for treatment of \200\230usual \200\231 COPD are applicable to individuals wit h AAT-de \201 cient lung disease including bron- chodilators, oxygen, pulmonary rehabilita tion, nutritional advice, in \202 uenza vaccinations and surgery (bullectomy and transplan tation). Lung volume reduction surgery offers only short-term bene \201 ts in AAT de \201 ciency emphysema and is generally not recommended. Liver transplantation remains the only treatment for liver cirrhosis. treatment until FEV1<35% when the costs of other general COPD treatments are included. Aero solised delivery of recombinant AAT has been devel- oped for daily administration but is of unproven ef \201 cacy. Novel strategies Novel therapeutic approaches include strategies using: \200 All-trans re tinoic acid to initiate the growth of new alveoli in emphysematous lungs. Rat studies have demonstrated encouraging results and human trials are ongoing. Identifying small molecules capable of preventing the polymerisation of AAT within hepatocy tes or rescuing misfolded AAT protein (chaperone therapy). Adeno-associated viral vectors to deliver and express Augmentation therapy The IV administration of pooled plasma puri \201 ed AAT has been the mainstay of treatment for severe AAT de \201 ciency in a limited number of countries since 1987. A protective threshold above 0.5g/l of AAT is thought to limit proteo- lytic lung in jury and so guard against the development of emphysema. Exogenous doses are administered on ce a week to achieve a trough level above this threshold but the interval can be extended t o 14 or 21 days to achieve ade- quate concentrations. There is good evidence that IV augmen tation therapy raises serum levels above the pro- tective threshold and AAT is detectable i n bronchoalveolar lavage \202 uid. The largest studies looking for evidence of clinical e f \201 cacy have been obser vational cohort studies which indicate a lower overall mortali ty and a slower rate of annual decline in FEV1 in recipients with moderate COPD (FEV1 of 35 \200\22365% predicted). In addition IV AAT use has been associated with a reduction in the frequency of respiratory tract infections, a signi \201 cant decline in sputum markers of in \202 ammation and relatively few serious side effects. The only randomized control tri al of IV augmenta- tion therapy showed no signi \201 cant difference in the rate of FEV1 d ecline or the rate of loss of lung density as de \201 ned by CT densitometry although ther e was a trend in favor of the active treatment group. Analyzes of IV AAT therapy suggests a n incremental cost effectiveness ratio of 103,400 per quality of life-years for AAT in the liver and other tissues. Transplantation of hepatocytes as an alternative to whole liver transplantation. Support groups and useful websites: \200 Alpha-1 UK (www.alpha1.org.uk). \200 Alpha-1 F oundation (www.alphaone.org). \200 Alpha-1 National Association (www.alpha1.org). \200 British Liver Trust (www.britishlivertrust.org.uk). Further reading ATS/ERS statement: Standards for the diagnosis and management of individual s with AAT de \201 ciency. Am J Respir Crit Care Med 2003; 168: 818 \200\223900. DeMeo DL, Sandhans RA, Barker AF, et al. Determinants of air \202 ow obstruction in severe alpha-1-antitrypsin de \201 ciency. Thorax 2007; 62: 806 \200\223813. Lomas DA, Mahadeva R. A1-Antitrypsin polymerization and the ser- pinopathies: pathobiology and prospects for therapy. J Clin Invest 2002; 110: 1585 \200\2231590. Needham M, Stockley RA. A1-Antitrypsin de \201 ciency. 3: Clinical manifestations and natu ral history. Thorax 2004; 59: 441 \200\223445. Perlmutter DH, Brodsky JL, Balisteri WF, et al. Molecular pathogen- esis of Alpha -1- Antitrypsin de \201 ciency- associated liver dis ease: A meeting review. Hepatology 2007; 45: 1313 \200\2231323. Stoller JK, Aboussouan LS. A1-antitrypsin de \201 ciency. Lancet 2005; 365: 2225 \200\2232236. 123 Chapter 6 Oxygen Chapter contents 6.1 Home oxygen therapy 124 J WEDZICHA 124 6.1 Home oxygen therapy Since the two landmark clinical trials of long-term oxygen therapy (LTOT) that reported in the early 1980s, there have been considerable advances in the understanding, prescription a nd provision of home oxygen therapy. The purpose of home oxygen therapy is to correct hypox aemia and not primarily as a therapy for breathlessness. LTOT is an important therapy as to date it is one of the few inter- ventions that can improve survival in patients with COPD and chronic respiratory failure. There are three main types of oxygen therapy that can be p rescribed for home use and these will be discussed in this article. Home oxygen therapy may also in used in infants and children but pediatric prescription is relatively small and th is article will concentrate on home oxygen in adults. LTOT is prescribed for patients for c ontinuous use at home usually through an oxygen concentrator. These patients will have chro nic hypoxaemia (PaO2 at or below 7.3kPa, (55mmHg)), though LTOT may also be indicated in pa tients with a PaO2 between 7.3 and 8kPa (55 to 60 mmHg), if they have evidence of pulmonary hypertension, secondary hypoxaemia, oedema or significant nocturnal arterial oxygen desatu ration. There is no bene \201 t in the use of LTOT in COPD patients with a PaO2 above 8kPa . Once started, this therapy is likely to be life long. There are three main indications for the prescription of long term oxygen therapy: 1 chroni c hypoxaemia; 2 nocturnal hypoventilation; 3 palliative use. Chronic hypoxaemia As already discussed identi \201 cation of patients with chronic hypoxa emia is important, as LTOT is one of the few treat- ments that can improve prognosis in pat ients with COPD. Chronic hypoxaemia, with or without carbon dioxide retention, can occur in several respiratory and cardiac dis- orders, including COPD, chronic severe asthma, inters titial lung disease such as \201 brosing alveolitis and asbestosis, cys- tic \201 brosi s and pulmonary hypertension. Chronic hypoxae- mia leads to an increase in pulmonary arteri al pressure, secondary polycythaemia and neuropsychological changes, and these complication s can be improved with LTOT. Patients who have daytime hypoxaemia may develop fur- ther art erial oxygen desaturation at night during nocturnal hypoventilation and this will contribut e to the observed rise in pulmonary artery pressure. Thus LTOT is always prescribed to incl ude the night-time as it will reduce the nocturnal hypoxia episodes and thus reduce the pea ks of pulmonary hypertension. LTOT has been shown to improve survival in hypoxaemic patient s, to reduce secondary polycythaemia and increase sleep quality. Chronic hypoxaemia is rela ted to poor health status (Fig. 6.1.1), anxiety and depression and these param- eters will improve with LTOT. It is also possible that LTOT may reduce the severity of COPD exacerbati ons as hypox- aemic patients, who are not taking LTOT, have been shown to be at increased r isk for hospital admission. Patients with severe cardiac failure may also develop arte- ria l hypoxaemia, caused mainly by ventilation perfusion inequalities. However there are few st udies of LTOT in cardiac failure and large studies with appropriate outcome measures are re quired. Ambulatory oxygen therapy KEY FACT LTOT is usually given for at least 15 hours daily, to include the overnight period , as arterial hypoxaemia worsens during sleep. Ambulatory oxygen therapy refers to the provision of oxygen therapy with a portable device during exercise and daily activities. It is usually prescribed in conjunction with LTOT, th ough a small group of normoxaemic patients may bene \201 t from ambulatory oxygen of they have signi \201 cant arterial oxygen desaturation on exercise. Short-burst oxygen therapy (SBOT) refers to the intermit- tent use of supplemental oxygen at home usually provided by static cylinders and normally for periods of about 10 \200\22320 minutes at a time to relie ve dyspnoea. Although considerable amounts of SBOT is used in the UK, the evi- dence for be ne \201 t of SBOT is weak and other treatments for dyspnoea should be used. 90 80 70 e r o c s 60 l a t o t 50 Q R G S 40 30 Indications for LTOT (Table 6.1.1) 20 Table 6.1.1 Indications for LTOT 10 8 9 10 4 5 6 7 Pao2 (kPa) COPD Severe chronic asthma Interstitial lung disease Cystic \201 brosis Bronchiectasis Pu lmonary vascular disease Primary pulmonary hypertension Pulmonary malignancy Chronic heart failure \200 \200 \200 \200 \200 \200 \200 \200 Fig. 6.1.1 Relation between quality of life and arterial hypoxaemia COPD patients. Reproduc ed from Okubadejo AA et al., Thorax 1996; 51: 44 \200\22347. Patients with chest wall or neuromuscular diseases .who develop hypercapnic respiratory fai lure usually require ventilatory support with NIV rather than LTOT. Use of LTOT in these pa tients may lead to a potentially dangerous rise in PaCO2. CHAPTER 6.1 Home oxygen therapy 125 However if chronic hypoxaemia persists while the patient is on ventilatory support, then LT OT should be prescribed but to start at a low oxygen \202 ow rate e.g. 1l/minute. Patient s on home oxygen should stop smoking as the use of oxygen in the presence of smoking is can cause burns and is a \201 re hazard. Any patient who persists in smoking despite using a ny form of home oxygen must be warned of the potential risks. Bene \201 ts of LTOT are lis ted in Table 6.1.2. \202 ow rate of 2 l/minute via nasal cannulae, or from a 24% controlled oxygen face mask, and to aim for a PaO2 value of at least 8kPa. Blood gasses must be measured, rather than S aO2 with a pulse oximeter, as assessment of hypercapnia and its response to oxygen therapy is required for safe prescrip- tion of LTOT. Pulse oximetry has also poor speci \201 city in the crucial PaO2 range for LTOT prescription and thus is unsuitable when used alone for assessment. However, oximetry may prove valuable in screening patients with chronic respira tory disease and selecting those patients who require further blood gas analysis. Patients on LTOT require formal assessment after prescription to ensure that there is adequate corre ction of hypoxaemia and that they are adherent to the treatment. Table 6.1.2 Bene \201 ts of LTOT Increased survival Increased quality of life Prevention of deterioration of pulmonary haemo dynamics Reduction of secondary polycythaemia Neuropsychological bene \201 t with reductio n in symptoms of anxiety and depression Improved sleep quality Reduction in cardiac arrhyth mias Increase in renal blood \202 ow \200 \200 \200 \200 Indications for ambulatory oxygen therapy Patients with chronic lung disease especially tho se with COPD or interstitial lung disease show increased arterial hypoxaemia when they exer cise. Ambulatory oxygen can correct this exercise hypoxaemia, and this has been shown to al so reduce breathlessness and increase exercise capac- ity though responses to ambulatory ox ygen are variable amongst patients. As for LTOT, the purpose of ambulatory oxygen is to cor rect exercise hypoxaemia and not as a therapy with the sole aim of reduction in dyspnoea. H owever most of the studies of the effects of ambulatory oxygen are relatively short-term st udies and there is less evidence that ambulatory oxygen improves quality of life over the l onger term. Ambulatory oxygen can be prescribed in three broad groups of patients: \200 G rade 1. Some patients on LTOT are already house- bound and unable to leave the home unaided . In this group ambulatory oxygen will be used for short periods only and intermittently. T hese patients will generally use ambulatory oxygen at the same \202 ow rate as with their LTOT. \200 \200 Nocturnal hypoventilation LTOT may also be used in patients with PaO2 above 7.3kPa but who have evidence of nocturnal hypoventilation. This patient group will include those with ches t wall disease caused by obesity, chest wall or neuromuscular disease. LTOT may also be use d in conjunction with continuous positive airway pressure (CPAP) for obstructive sleep apno ea. though LTOT is not \201 rst-line therapy for sleep ap- noea. Prescription of LTOT in these situations will require referral to a physician with a specialist interest in these d isorders as specialist investigation is required. Although LTOT is usually given life-long for patients with COPD, in the case of some chest wall disorders and sleep apnoea, LTOT wil l be prescribed for a temporary period, perhaps till the respiratory failure improves with ventila- tory support or weight reduction in the case of sleep apnoea patients has been suc cessful. Grade 2. Patients on LTOT, who are mobile and need to or can leave the home on a regular ba sis. In this patient group assessment will need to include a review of activity and oxygen \202 ow rate required to correct hypoxaemia. \200 Grade 3. Patients without chronic hyp oxaemia (PaO2> 7.3kPa), who are not on LTOT, but who show evidence of arterial oxygen desat uration on exercise, with a fall of SaO2 of at least 4% below 90%. Ambulatory oxygen should only be prescribed if there is evidence of exercise de-saturation that is corrected by the proposed device. Ambulatory oxygen therapy is indicated in a number of respiratory conditi ons, with COPD being the most common. Ambulatory oxygen is not indicated in patients with n o evidence of arterial hypoxaemia and is not indicated in patients with chronic heart failu re. The other indications are listed in Table 6.1.3: Palliative use LTOT may also be prescribed for palliation of severe dys- pnoea in patients with lung cancer and other causes of disabling dyspnoea such as is found in patients with s evere end-stage COPD or neuromuscular disease. Assessment for LTOT It essential that all patients who may have require LTOT undergo a full assessment in a specialist center. The pur- pose of assessment is to con \201 rm the pres ence of hypoxae- mia and to ensure that the correct oxygen \202 ow rate is provided to ad equately correct the hypoxaemia. Assess- ment for LTOT depends on measurement of ABGs. Eith er blood gasses from a radial or femoral artery or arterialised ear-lobe capillary blood ga sses can be used for assessments. The advantages of ear-lobe gasses are that samples can be performed by various health care professionals. Prior to LTOT assessment and prescription, it is essential that there has been optimum medical management of the particular condition and clinical stability. Patients should not be as- sessed for LTOT during an acute exacerb ation of their dis- ease. As exacerbation recovery may be prolonged, hypox- aemia can persi st after exacerbation and thus assessment should occur no sooner than at around 5 \200\2236 weeks after exacerbation. It is usual to start with a supplemental oxygen Table 6.1.3 Indications for ambulatory oxygen COPD Severe chronic asthma Interstitial lung disease Cystic \201 brosis Pulmonary vascula r disease Primary pulmonary hypertension Chest wall disease e.g. kyphoscoliosis \200 \200 \200 \200 \200 \200 J WEDZICHA 126 Assessment for ambulatory oxygen The type of ambulatory oxygen assessment will depend on th e patient \200\231s grade and thus on the patient \200\231s activity and ability to leave t he home (Table 6.1.4). Traditionally assess- ments for ambulatory oxygen therapy use short- term response to supplemental oxygen therapy during an exer- cise test (e.g. 6MWT) . Howeve r it is now recognized that short-term responses do not predict bene \201 t over a longer period of time and thus the short-term response cannot be used to select patients for ambul atory oxygen. In some cases the weight of the ambulatory device has been shown to negate th e bene \201 t of the therapy on the short-term response. Thus the ambulatory oxygen assess ment should be used as an opportunity to assess the patient \200\231s activity, to set the optimal oxygen \202 ow rate and introduce the patient to the ambulatory device. The asses sment should ideally be performed after a course of exercise training as part of a pulmonar y rehabilitation program. The initial assess- ment should be followed by a review after app roximately 2 months of oxygen usage and ambulatory oxygen withdrawn if unhelpful. Before prescription of ambulatory oxygen, it is important to determine the level of outside activity that the patient is likely to perform, so that the most effective and economic de vice is provided for the patient. Most ambulatory oxygen is provided with lightweight porta ble cylinders, though small cylinders provide oxygen for a short duration and oxygen-conser ving devices may be useful in prolonging oxygen availability. However, patient responses to these conserving devices vary due to varying inspiratory \202 ow rates and patients shou ld to be assessed on the same equip- ment that they will eventually use when at home. Liqui d oxygen systems can provide a longer period of ambulatory oxygen usage but are expensive t o provide and not so widely available. SBOT Despite extensive prescription of short burst therapy, there is no evidence available for bene \201 t of this oxygen modality and other interventions should be used for control of dyspnoea. SBOT has traditionally been used for pre-oxygenation before exercise, recover y from exercise and control of breathlessness at rest. It has been also used in palliative care to relieve disabling dyspnoea though pa- tients in this condition usually require a so urce of LTOT at home. SBOT has also been used after a COPD exacerba- tion when a patients h as not yet recovered form hypoxae- mia, though in that case, temporary LTOT would be more a ppropriate. Table 6.1.4 Ambulatory oxygen therapy \200\223 patient assessment GRADE 1 OXYGEN REQUIREME NTS \200\223 same \202 ow rate as for static source GRADE 2 OXYGEN REQUIREMENTS \200\223 evaluate oxygen \202 ow rate to correct exercise Sa O2 above 90% using exercise test e.g. 6MWT Further reading Clinical component for the home oxygen service in England and GRADE 3 OXYGEN REQUIREMENTS \200\223 exercise test required, performed on air and oxygen. Require evidence of exercise desturation and improvement with oxygen Wales, accessed www.brit-thoracic.org.uk Domiciliary Oxygen Therapy Services. Clinical Guidelines and Advice for Prescribers. A repo rt of the Royal College of Physicians. 1999 There is little information on compliance with ambulatory oxygen therapy, though when asses sed, compliance has been found to be generally poor, with most patients only using it occas ionally to go out of the house or into their gardens and much less than instructed by their healthcare professionals. Thus appropriate education should be provided with prescription of the ambulatory equipment. Medical Research Council Working Party. Long term domiciliary oxygen therapy in chronic hyp oxic cor pulmonale complicating chronic bronchitis and emphysema. Lancet 1981; 1: 681 \200 \223686. Nocturnal Oxygen Therapy Trial Group. Continuous or nocturnal oxygen therapy in hypoxaemic chronic obstructive lung disease. Ann Intern Med 1980; 93: 391 \200\223398. 127 Chapter 7 Diffuse parenchymal lung disease Chapter contents 7.1 Usual interstitial pneumonia 128 7.2 Non-speci \201 c interstitial pneumonia 132 7.3 R espiratory bronchiolitis-associated interstitial lung disease 136 7.4 Desquamative intersti tial pneumonia 138 7.5 Acute interstitial pneumonia 140 7.6 Lymphoid interstitial pneumonia 142 7.7 Cryptogenic organizing pneumonia 144 7.8 Extrinsic allergic alveolitis 148 7.9 Sar coidosis 152 7.10 Pulmonary manifestations of connective tissue disorders 156 7.11 Pulmonar y manifestations of systemic diseases 160 A MILLAR 128 7.1 Usual interstitial pneumonia Epidemiology Limited data is available and most of the studies pre- date the new ATS/ERS re -classi \201 cation of IIPs (idiopathic interstitial pneumonias). Data from computerized U K general practice records suggest that the 12-month period prevalence of the previously us ed unclassi \201 ed term, cryprogenic \201 brosing alveolitis, (CFA) is 15 to 18 per 100 ,000 person years. Median survival of newly diagnosed patients with CFA is 3 years, a \201 gure which is similar to that currently reported for patients with UIP. The median age of presentation of CFA is 70 years, with the disease uncommon below the age of 50 years. I t is more common in men with a male:female ratio of 1.5 \200\2232.0:1. There is an increase d risk of developing lung cancer in these patients. AUTHOR \200\231S TIPS \200 Lung volumes may be preserved or an obstructive de \201 cit ( typically increased RV) may co-exist in smokers. \200 Normal maximal exercise testing eff ectively excludes clinically signi \201 cant UIP (or other DPLD). It forms a major part of the physiological components of the original and revised clinical \200\223radiological \200\223physiological score, but evidence for its clinical role is limited. Chest radiography Clinical approach Key points \200 Natural history of the condition to date? Typically gradual onset of breathlessness. Presence of any respiratory risk factors/aetiological agents? Severity of symptoms? Examination: key points \200 Finger clubbing is suggestive of UIP (49 \200\22366% of pati ents) Fig. 7.1.1 CXR showing bilateral diffuse alveolar shawoing obscuring heart border. particularly in men. Fine, basal \200\230velcro-like \200\231 inspiratory crackles are charac- Peripheral and basal reticular shadowing are characteristic but can be normal in biopsy pro ven cases. teristic of UIP (>90% cases). Additional added sounds (squeaks or wheeze) are sug- gestive of alternate or co-existing diagnoses. Cyanosis re \202 ects relatively severe hypoxaemia. Pulse oximetry can readily detect less severe hypoxaemia. \200 Physical signs of pulmonary hypertension and right ven- tricular failure which may re \202 ect hypoxia from severe pulmonary \201 brosis for example in UIP. Investigation Lung function \200 A restrictive defect with reduced gas transfer is charac - teristic of UIP. Severe lung function impairment is associated with poor outcome. A gas transfer of less than 35 \200\22340% predicted has 80% sensitivity and speci \201 ci ty for prediciting death within 2 years and serves as the main basis for a proposed distinc tion between \200\230advanced \200\231 and \200\230limited \200\231 disease in IPF. A 10% reduction in FVC, or 15% change in DLCO is needed to identify a true change in diseas e severity (as opposed to measurement variation). Serial FVC is likely to be more sensitive to change than serial DLCO, par ticularly impor t ant in advanced disease where identifying 15% change may be impractical. Oxygen saturations are often reduced particularly on exercise. The 6MWT is reproducible in UIP patients and desatura- tion to 88% during or at the end of the test may be a more powerful predictor of mortality than resting lung function tests. Fig. 7.1.2 CT scans showing reticular shadowing particularly in the subpleural regions with secondary bronchial dilatation and some honeycombing. CHAPTER 7.1 Usual interstitial pneumonia 129 patients often show relief that they are not suffering from lung cancer. In patients with U IP, a general management approach comparable to that of patients with inoperable lung cance r is appropriate. This includes providing patient information and support, palliative treat ment of symptoms and complications of the disease and best supportive care; both for young patients with IPF awaiting lung transplant, patients in clinical trials of novel therapy an d patients with advanced disease facing-end-of life issues. Further, drawing on the analogy with lung cancer, this general management approach may be best delivered in a multidiscipl inary setting with appropriate input from palliative care medical and nursing specialists. HRCT HRCT features from ATS/ERS guidelines: \200 HRCT is a very sensitive, but not 100%, technique for the diagnosis of UIP with a low false-positive rate. Typical HRCT appearances of UIP by expert radiologists are correct in the majority (>90%) of cases. HRCT may be useful in providing an explanation in patients in whom there is a sudden and un expected deterioration in clinical status. It provides useful information on the distribution of disease that may be used to guide sub sequent BAL, transbronchial biopsy or surgical lung biopsy if being considered. AUTHOR \200\231S TIPS Communicating the diagnosis \200 The long-term prognosis is little different than that of many malignancies leading to patients with advanced IPF receiving su b-optimal care. AUTHOR \200\231S TIPS \200 Beware of false positive interpretation of CXR in obese patients. Increasing use of HRCT has led to situations in which limited features are seen in patients in whom the clini- cal signi \201 cance is uncertain but probably limited. Patients should be offered tailored but clear and accurate information regarding the diagno sis, very limited treatment options and prognosis. BAL and TBB \200 BAL and TBB have only a limited role in the diagnosis of UIP. If the cli nical and HRCT \201 ndings are characteristic of UIP it adds little. Smoking cessation There is a 10-fold increased risk of developing lung cancer whether they smoke or not, increasing to 200 in a 20/day smoker. There are reports in the literature tha t patients with IPF who smoke have a better prognosis than those who do not smoke. This is almost certainly due to the co-existence of COPD leading to an earlier presentation of IPF and these reports should not discourage the use of smoking cessation services. The decision to perform BAL, TBB or both is also informed by the likely differential diagno sis and patient \201 tness, but also on availability of local expertise in dif- ferential BAL cell count. The optimal BAL technique has been addressed in several guidelines. Traditionally, BAL has been performed in one lobe, either the right middle lobe or one of t he basal segments of the right lower lobe. Whilst single, site BAL has been consid- ered to be representative of the lung as a whole, based largely on studies comparing the same lobe in either lung, there is some evidence that this is not the case. BAL may be more useful i f targeted to a segment most affected, as identi \201 ed by HRCT. Treatment of symptoms and complications of UIP Breathlessness \200 Breathlessness in UIP is exacerbated by exercise and cough. When accompanied by hypoxaemia, domiciliary and/or am bulatory oxygen should be prescribed to relieve this symptom. It is reasonable to titrate o xygen therapy according to resting oxygen saturations, but augmented \202 ow may be requi red immediately following exercise. Patients may therefore need both an oxygen concentrator and a cylinder. However, there is no evi- dence that administration of oxygen in \202 uen ces long- term survival or improves quality of life. Similarly the optimum site for TBLB should be informed by the HRCT appearance. Where the HRCT appearance suggests \201 brosis with a UIP-like pattern, then the BAL cell count does not differentiate between \201 brotic NSIP and UIP either diag- nostically or prognostically. Oral opiates may be effective in relieving distress from breathlessness. Liaison with palli ative care services, if available, may lead to a more holistic approach to symp- tom relief . BAL neutrophils, which are strongly linked to the extent of disease on HRCT and the severit y of functional impairment, mainly re \202 ect disease severity. It may be useful in patients with a sudden deterioration or exacerbation to exclude infecti on or malignancy. \200 There is insuf \201 cient evidence to support the routine use of BAL cell counts to determine need for treatment in UIP. Pulmonary rehabilitation programs have not been evaluated in IPF but are likely to contribu te to overall well-being. Cough \200 Cough is a frequent and troublesome symptom. In cur- rent or ex-smokers produc tive cough may arise from co-existent chronic bronchitis. Gastro-oesophageal re \202 ux di sease (GORD) may be associated with cough. Whilst the role of GORD in the pathogenesis and progression of IPF remains uncertain, symptomatic patients should be treated with a proton pump inhibitor. Transbronchial biopsies do not allow a speci \201 c diagnosis of UIP. Open lung biopsy Surgical biopsy con \201 rmation, when clinical and HRCT features are typ ical of UIP, cannot easily be justi \201 ed. Management and treatment Overview In the majority, UIP will progress over a period of month s and years towards a terminal phase. At the time of diagnosis Conventional anti-tussive agents, such as oral codeine, are widely used, but there is no ev idence of ef \201 cacy. Oral opiates may be used for intractable cough particu- larly in e nd-stage disease. A MILLAR 130 with interferon-gamma 1B (10%), but this trend did not reach statistical signi \201 cance (p=0.08). The hypothesis that interferon-gamma-1B may confer a survival bene \201 t, par- ticularly in patients with milder disease, remains unproven and the results of ongoing rand omized controlled studies are awaited. Pneumothorax Spontaneous pneumothorax or pneumo-mediastinum is a recognized complication of IPF and should be suspected when a patient complains of a sudden increase in breath- lessn ess. Pleurodesis is not a contra-indication to future lung transplantation. Pneumothorax ca n be a late compli- cation of IPF and cause severe breathlessness. In such cases the lung m ay fail to re-expand after insertion of an intercostal drain because of altered lung compli ance and palliative care may be more appropriate. N-acetylcysteine (NAC) A number of in vitro and animal model experiments led to the suggest ion that a redox imbalance may contribute to the development of IPF. The subsequent clinica l obser- vation that lung epithelial lining \202 uid from IPF subjects was deplete of red uced glutathione laid the foundation for clinical trials of NAC. A 12 month double-blind st udy to assess the affects of NAC (600 mg tds) in patients with a con \201 dent UIP diagno- sis analyzed 155 receiving prednisolone (tapering from 0.5 mg/kg a day) and azathioprine ( 2 mg/kg a day). 80 patients received NAC and 75 patients placebo. VC was 9% and DLCO 24% hi gher in the NAC group but no signi \201 cant differences in mortality were found. However, patients in whom the standard regimen with prednisolone and azathioprine was contraindicat ed or \200\230not justi \201 ed \200\231 were excluded from the study and 40% of particip ants were recruited within 6 months of diagnosis. Lung cancer IPF predisposes to non-small cell and small cell lung cancer. Diagnosis and sta ging should be undertaken as for any other patient, although poor lung function from co-exi sting pulmonary \201 brosis makes the possibility of curative treat- ment less likely. Potential disease modifying UIP as the most common form of IIP has/is being studied in more recent trials with recruitment of a virtually homogenous population of patients, albeit at varying stages in the natural history of the disease. Three of these have reported, interf eron-gamma 1B, pirfenidone and N-acetylcysteine, the latter as an adjunct to prednisolone a nd azathioprine, others will follow including endothelin-1 antagonists and TNF-A blockade. Steroid monotherapy More recent studies do not support the use of corticoste- roids in IPF. A meta-analysis concluded that there was no evidence that steroids prolonged survival or i mproved quality of life in this condition. High-dose steroids should not be given (0.5 \200 \2231mg/kg). Key recommendations \200 Steroid monotherapy should not be given. \200 If treatment wit h azathioprine/prednisolone therapy is given, patients should also receive N-acetylcysteine (600mg tds). Treatment should be given within multi-center trials where possible. Steroids and azathioprine There is not substantial evidence for treatment bene \201 t but some clinicians still use this regimen (see BTS guidelines). Lung transplantation \200 A multi-variable analysis from a single center study of 46 pati ents with IPF accepted for transplantation (28 successfully transplanted, 16 died awaiting transplan- tation) suggested that lung transplantation reduced the risk of death by 75%. Cyclophosphamide There is no evidence that oral or pulsed cyclophosphamide is of any long-t erm bene \201 t in terms of survival or quality of life for patients with IPF and it has a signi \201 cant side effect pro \201 le. Transplant should be considered in those patients below who ful \201 l established selecti on criteria for transplant, thus generally excluding those over the age 65 and/or those wit h signi \201 cant co-morbidity. Pirfenidone Pirfenidone is a pyridone which inhibits \201 broblast prolifera- tion and co llagen synthesis in vitro and ameliorates bleo- mycin-induced pulmonary \201 brosis in an imals. A placebo (2:1) controlled, double-blind phase 2 study of pirfenidone therapy in 107 Japanese patients with moderate IPF has recently been reported. Planned for 1 year, the st udy was prematurely stopped at 9 months due to signi \201 cantly greater acute exacerbatio ns in the placebo group. Patients receiving pirfenidone also had signi \201 cantly smaller decline in VC and a small but signi \201 cant improvement in degree of desaturation follo wing a 6MWT at 9 months. Further ran- domised trials of Pirfenidone in IPF are ongoing. Int erferon-gamma 1 Interferon gamma is a Th1 cytokine which down-regulates collagen gene exp ression and suppress products/effects of pro- \201 brotic growth factors. This led to the hypothesis that it might prevent progression of pulmonary \201 brosis initially. A prospe ctive double-blind placebo controlled trial of interferon-gamma-1B in 330 patients reported no signi \201 - cant affect on lung function at any time point. There were more deaths in the placebo group (17%) than those treated Definite UIP (clinico-radiologically or a pathologi- cal diagnosis) should be discussed wit h a transplant center. Advanced UIP (DLCO<39% predicted), or progressive disease (10% or greater decline in FVC du ring 6 months of follow up) should be referred to a transplant center for assessment. AUTHOR \200\231S TIP Don \200\231t miss the transplant window. Further reading American Thoracic Society/European Respiratory Society International Multid isciplinary Consensus Classi \201 cation of the Idiopathic Interstitial Pneumonias. Am J R espir Crit Care Med 2002; 165: 277 \200\223304. Azuma A, Nukiwa T, Tsuboi E, et al. Double blind, placebo- controlled trial of pirfenidone in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2005; 171: 1040 \200\2231047. CHAPTER 7.1 Usual interstitial pneumonia 131 (ASTP)/American Thoracic Society (ATS)/European Respiratory Society(ERS)/International Soci ety for Heart and Lung Transplantation(ISHLT). Am J Respir Crit Care Med 1998; 158(1): 335 \200\223339. Bradley B, Branley HM, Egan J J, et al. Interstitial lung disease guide- line: the British Thoracic Society in collaboration with the Thoracic Society of Australia and New Zealand an d the Irish Thoracic Society. Thorax 2008; 63: (Suppl 5) VI \200\22358. BTS Interstitial lung disease guidelines. Thorax 2008; 63: v1 \200\223v58. Crockett AJ, Cra nston JM, Antic N. Domiciliary oxygen for intersti- tial lung disease. The Cochrane Databas e of Systematic Reviews 2001, Issue 3. Art. No.: CD002883. DOI: 10.1002/14651858. CD002883.