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. General management Early involvement of a pain relief and palliative care service is requir ed. Ensure adequate analgesia: opiates and NSAIDs for chest wall pain; consider carbamazepi ne or sodium valproate for neuropathic pain (from intercostal nerve or vertebral involvemen t); nerve blocks or cor- dotomy may be required. Breathlessness may be multifactorial, e.g. pleural effusion, lung compression, chest wall restriction, pericardial involvement, anemi a, pain, anxiety, and fear. Liaise with GP, specialist nurse, palliative care teams. Remind GP that all deaths have to be reported to the coroner. Discuss compensation issues (p 118) . MESOTHELIOMA: TREATMENT AND OUTCOME 117 Clinical course Median survival is 9 \200\22312 months from diagnosis. Typically progresses by local extension, sometimes leading to involvement of the contralateral lung or peritone um, SVCO, cardiac tamponade, or spinal cord compression. Distant metastases are common (50% at autopsy), although occur late and are rarely clinically apparent. Peritoneal mesothelio ma is rarer than pleural mesothelioma, and may be associated with more prolonged asbestos e xposure. Remains intra-abdominal in most cases. Clinical features include abdominal discom- fort, weight loss, ascites, and in some cases organ involvement (e.g. intes- tinal obstruc tion). Fine-needle aspiration of omental masses may provide a diagnosis, although laparosco py is often required. Prognosis is worse than for pleural mesothelioma, with median surviva l 7.4 months. No treatment is of proven bene \201 t. Mesothelioma has also been described affecting other serosal surfaces, such as pericardium and tunica vaginalis. Future developments \200 Measurement of serum mesothelin-related protein (SMRP; a soluble product of the surface pro tein mesothelin) may have a diagnostic role: SMRP is frequently raised in patients with mes othelioma, but only very rarely in healthy controls or patients with other malignant or in \202 amma- tory lung or pleural disease Microarray studies of gene expression in tumor sam ples may prove to be useful in both distinguishing mesothelioma from adenocarcinoma and in predicting prognosis Novel therapeutic strategies using immunotherapy (e.g. recombinant int erferon-alpha), gene therapy, anti-angiogenic agents, and photo- dynamic therapy are in dev elopment. Combinations of immunotherapy with chemotherapy appear particularly promising. CHAPTER 17 Asbestos and the lung 118 Compensation for asbestos-related diseases Identi \201 cation of asbestos exposure is esse ntial for the patient to be able to claim compensation. Patients are not eligible for compe nsation if their exposure occurred whilst they were self-employed. There are two prin- cipa l sources of compensation. From the Government: apply to the Bene \201 ts Agency (Department of Social Security) for industrial injuries disablement bene \201 t, using form BI100PN. Available for the followi ng diseases: \200 \200 \200 \200 Diffuse pleural thickening Asbestosis Lung cancer associated with diffuse pleural thickenin g or asbestosis Mesothelioma. There must be a clear history of asbestos exposure at work. Compensation is not available f or pleural plaques alone. If successful, may then apply for a single payment from the gover nment under the Pneumoconiosis, etc. (Worker \200\231s Compensation) Act 1979. The value of compensation re \202 ects the degree of disability from which the patient is considered t o suffer and their age at diagnosis. Next-of-kin may also claim within 6 months posthu- mou sly. The War Pensions Scheme may provide compensation for disease resulting from asbestos e xposure with HM forces (form WPA1). From the Courts: Common law compensation directly from a pre- vious employer. Can be claime d from the employer \200\231s insurer, even if the employer is now out of existence. Advise patient to seek advice as soon as possible from a solicitor with relevant experience. Clai ms must be initi- ated within 3 years of the individual \200\231s \201 rst awareness that they have an asbestos-related disease attempts to initiate claims after 3 years may be sta tute barred. Inform the patient of this and document the conversation in the medical notes. A Court of Appeal ruling in March 2006 concluded that pleural plaques alone should now no longer be considered an indica- tion for compensation, and a subsequent appeal failed to ov erturn this ruling in the House of Lords. Awards for asbestosis range from 15,000 to 50 ,000, depending on symptoms and the degree of disability; such patients may accept a greate r \200\230once and for all \200\231 award and forego their right to further claims in the event of mesothelioma developing. Typical awards for mesothelioma are 45,000 \200\223 50 ,000 and additional amounts may be claimed for care and future loss of wages; total compens ation may exceed 100,000. Successful claims have also been made for mesothelioma occurrin g in relatives who were exposed to asbestos whilst washing work clothes. COMPENSATION FOR ASBESTOS-RELATED DISEASES 119 Further information DSS Bene \201 ts Agency enquiry line 0800 882200 or 0800 2792322. Advi ce on available bene \201 ts and completing claim applications. Lea \202 ets SD5 \200 \230Ill or Disabled Because of Work \200\231 and NI12 \200\230If you have an Industrial Di sease \200\231 may be helpful. Website www.dwp.gov.uk/index.asp contains further informatio n on the Pneumoconiosis etc. (Worker \200\231s Compensation) Act 1979, as well as many usef ul contacts and links London Hazards Center. http://www.lhc.org.uk/members/pubs/books/asbestos/asb_toc.htm Occupational and Environmental Diseases Association offers support and advice to patients a nd their relatives including information on solicitors and the process of compensation. PO Box 26, En \201 eld, Middlesex EN1 2NT. Telephone 020 8360 8490. Website www.oeda.demon.co .uk http://www.mesoinfo.com http://www.mesothelioma-facts.com This page intentionally left blank 121 Chapter 18 Asthma De \201 nition, epidemiology, pathophysiology, etiology 122 Clinical features 124 Investig ations 126 Acute severe asthma 128 Chronic asthma: management 132 Chronic asthma: additiona l treatment options 134 Non-pharmacological management 136 Dif \201 cult/refractory asthma 138 Asthma in pregnancy 140 Occupational asthma 142 Management of occupational asthma 144 Vocal cord dysfunction 146 Allergic rhinitis (hay fever) 148 CHAPTER 18 Asthma 122 De \201 nition, epidemiology, pathophysiology, etiology De \201 nition There is no univer sally agreed de \201 nition; it is usually a clinical diagnosis \200\224a chronic airway i n \202 ammatory disorder with in \202 ammation due to complex interactions between in \202 ammatory cells, mediators, and airway cells. This is characterized by airway hyperreac tivity to a variety of non-speci \201 c stimuli, leading to a variable degree of airway ob struction, some of which may become irreversible over many years. In susceptible individuals this leads to recurrent episodes of wheeze, chest tightness, breathlessness, and cough (particularly at night). \200 The disease is associated with widespread and variable air \202 ow obstruc- tion, which ma y reverse spontaneously or with treatment Airway in \202 ammatory changes lead to increase d bronchial responsive- ness to a variety of non-speci \201 c stimuli Epidemiology It is the commonest chronic respiratory disease in the UK, with a prevalence o f 10 \200\22315%. There is a wide variation in disease prev- alence, with highest levels se en in English-speaking countries (where there is also a high prevalence of sensitization to common aeroallergens). The reason for the increasing worldwide prevalence over the last fe w decades is unclear. Pathophysiology Best described as chronic eosinophilic bronchitis/ br onchiolitis. Airway in \202 ammation is seen, with cellular in \201 ltration by T helper- 2 (Th2) cells, lymphocytes, eosinophils, and mast cells. There is large and small airway in volvement, and cytokine production (platelet acti- vating factor and leukotrienes). Airway obstruction occurs due to a combination of: \200 \200 \200 In \202 ammatory cell in \201 ltration Mucus hypersecretion with mucus plug formation Smo oth muscle contraction This may become irreversible over time due to: \200 Basement membrane thickening, collagen deposition, and epithelial desquamation Airway remod eling occurs in chronic disease, with smooth muscle hypertrophy and hyperplasia. This is no w recognized as increasingly important in the pathophysiology of the most dif \201 cult to treat chronic asthma Etiology This is due to a combination of genetic and environmental factors, with many diffe rent genes identi \201 ed. Immunological mechanisms A subgroup of asthmatics are atopic, and therefore react to antige n challenge by producing speci \201 c IgE from B lym- phocytes. This leads to the formatio n of IgE \200\223antigen complexes that bind to mast cells, basophils, and macrophages, lea ding to the release of pre- formed mediators, such as histamine, and eosinophil chemotactic factor. These factors cause bronchoconstriction and airway oedema. DEFINITION, EPIDEMIOLOGY, PATHOPHYSIOLOGY, etiology 123 Prostaglandins, leukotrienes, kinins, and platelet activating factor (PAF), are all importa nt secondary messengers involved in the in \202 ammatory response. A subgroup of asthmatics (up to 25%) are now recognized to have non- eosinophilic disease, which may be associated with a poorer short-term response to inhaled corticosteroids, and i s associated with neutrophilic airway in \202 ammation and innate immunity. Genetic factors A hereditary component to asthma and atopy is well established, and a numbe r of chromosomes and linkages are implicated. The multiple mechanisms and second messengers involved in asthma make the contribution of the effects of speci \201 c genes dif \201 c ult to deter- mine. Established susceptibility loci include the genes ADAM33, GPRA (G-prote in related receptor for asthma), and ORMDL3, a member of a gene family that encodes transme mbrane endoplasmic reticulum proteins. The latter was very recently identi \201 ed by a ge nome-wide screen, and its function and role in the pathogenesis of asthma is not yet clear. Hygiene hypothesis This suggests that early life exposure to endotoxin switches off the all ergic response (by reducing Th2-mediated responses), leading to reduced allergen sensitivit y later in life, therefore reducing allergen-driven diseases such as asthma. Large epidemio logical studies support this hypothesis. Environmental factors The increasing prevalence of asthma appears to be associated with a r ising standard of living worldwide, and not just in west- ernized societies. This has impli cated a number of environmental factors. A number of explanations are speculated (but not p roven), including dietary changes, a reduction in childhood infections, increased immuniza- tion, or a combination of all three. Phenotypic differences It is increasingly recognized that \200\230asthma \200\231 is likel y to represent a number of different \200\230diseases \200\231 or subphenotypes, rather th an one disease with a unifying pathological mechanism. Subphenotypes may differ in underlyi ng pathophysiology, clinical features, and disease course, and research aimed at clearly id entifying such disease groups (for example, through the use of biomarkers or the host genet ic pro \201 le) is ongoing. CHAPTER 18 Asthma 124 Clinical features \200 \200 \200 \200 Cough Shortness of breath Wheeze Chest tightness. Classically these are variable, intermittent, worse at night, associated with speci \201 c triggers, e.g. pollens, cat and dog dander, and non-speci \201 c triggers, e.g. cold air, perfumes, and bleaches, due to airway hypersensitivity. Asthma may be labeled \200\230cou gh variant \200\231 or \200\230cough predominant \200\231, when cough is the major symptom . Examination \200 \200 \200 \200 May be entirely normal Classically expiratory wheeze is heard Chest deformity/hyperin \202 ation - longstanding/poorly controlled asthma Severe life-threatening asthma may have no w heeze and a silent chest. Diagnosis This is often a clinical diagnosis but should be supported by objective measureme nts. Important to: \200 Identify provoking factors, e.g. cold air, bleach, perfume, and environ- mental aeroallerge ns (grasses, pollen, hay), and any occupational exposures Assess disease severity. Longitud inal studies show greater decline in lung function in asthmatics than non-asthmatics \200 \224greater still in asth- matics who smoke. Don \200\231t forget to look for/ask about: \200 \200 \200 \200 \200 \200 \200 \200 \200 Nasal symptoms \200\223obstruction, rhinorrhoea, hyposmia Atopic dermatitis/eczema/hay feve r Allergies including food allergy Re \202 ux/GORD disease (treating re \202 ux may impro ve asthma control) Laryngo/pharyngeal re \202 ux (hoarse voice, throat clearing, acid in t hroat) Triggers \200\224including exercise, menstruation Social situation/stresses Aspirin sensitivity (associated with later onset asthma and nasal polyps) Family history. CLINICAL FEATURES 125 The diagnosis is based on the presence of: \200 \200 Symptoms (cough, wheeze, breathlessness) Day-to-day peak \202 ow variability (>15% variab ility or reversibility to inhaled B2 agonist) Airway hyperresponsiveness. Consider the diagnosis of asthma in: \200 \200 \200 \200 \200 Recurrent cough, episodic breathlessness, and wheeze Chest tightness Isolated or nocturnal cough Exercised-induced cough or breathlessness Hyperventilation syndrome (p 255). Aspirin-induced asthma (AIA) \200 \200 \200 \200 De \201 ned as chronic rhinoconjunctivitis, nasal polyps, and asthma Asthma is precipitate d by ingestion of aspirin or other NSAIDs Occurs in up to 20% of asthmatics, and is commone r in women The mechanism is thought to be via aspirin inhibition of the cyclo-oxygenase pat hway, with excess leukotriene production via the lipo-oxygenase pathway BAL and urine in AI A patients show excess leukotrienes post aspirin exposure Loss of anti-in \202 ammatory pr ostaglandin E2 may also be important. Oral allergy syndrome A subset of patients sensitized to aeroallergens, such as tree and grass pollens, develop l ocalized lip angioedema after ingestion of speci \201 c fruits that share cross-reactive e pitopes with pollen allergens. The reaction occurs immediately after ingesting the fruit. C ooked fruit is usually tol- erated, presumably because the culpable proteins are denatured with cooking. Birch pollens cross-react with apples, hazelnuts, and potato. Ragwort shares epitopes with melon and bananas. CHAPTER 18 Asthma 126 Investigations The number of investigations required depends on the certainty of the diagno sis from the history, simple spirometry, and peak \202 ow recordings. Most patients refer red for a respiratory opinion will already have com- pleted home peak \202 ow recordings and have had a CXR. Repeating PEFs may still be of bene \201 t. Objective evidence of asth ma is important before starting long-term therapy with potentially harmful drugs, such as i nhaled steroids. Essential investigations (on which the diagnosis is based) \200 Peak \202 ow recording/simple spirometry to look for variability and response to treatmen t. Airway obstruction leads to decreased peak expiratory \202 ow rate (PEFR) and forced e xpiratory volume in one second (FEV1), but these may be normal between episodes of bronchos pasm. If they are persistently normal, the diagnosis must be in doubt. The diagnosis is cer tain if: \200 20% diurnal PEF variation on >3 days per week, in a week of peak \202 ow diary measures F EV1 >15% decrease after 6 min exercise FEV1 >15% (or 200 mL) increase after 2 week trial of oral steroid (30 mg prednisolone od) \200 Bronchodilator reversibility testing FEV1 >15% (or 200 mL) increase after short-acting B2 a gonist therapy (e.g. salbutamol 400 g by MDI with spacer or 2.5 mg by nebulizer) Non essential/optional investigations \200 Blood tests \200 FBC (eosinophilia \200\224question the diagnosis if high total eosinophil count; consider C hurg \200\223Strauss syndrome) IgE (associated atopy, i.e. positive skin prick tests to com mon allergens, often with associated allergic rhinitis and eczema) Aspergillus precipitins (Aspergillus sensitivity, ABPA) see Chapter 41 Speci \201 c IgE if other environmental tri ggers suspected CXR if atypical symptoms. May show hyperin \202 ation or evidence of local ized abnormality simulating wheeze, e.g. adenoma (rare) Skin tests to de \201 ne atopic co nstitution, or identify potential triggers Metacholine/histamine challenge measures bronchi al hyperresponsiveness (BHR) as a PC20, the dose of agent provoking a 20% fall in FEV1. Ast hma is suggested by a PC20 below 8 mg/mL. Normal subjects have a PC20 >16 mg/mL. The absenc e of BHR virtually excludes the diagnosis of asthma; however, the presence of BHR does not prove asthma. Bronchial provocation tests aim to demonstrate bronchospasm to an inhaled age nt, usually occupational. The response to an aerosolized sample of a suspected agent may be useful if the diagnosis of occupational asthma is suspected, but PEF recordings at home, w ork, and on holiday may be more useful. Should only be carried out in a tertiary referral c enter, under expert supervision \200 \200 \200 INVESTIGATIONS 127 \200 Sputum analysis Sputum eosinophilia may help con \201 rm the diagnosis Laryngoscopy/ENT ex amination Useful if concerns about nasal symptoms or obstruction, e.g. from polyps, or to e xclude upper airway obstruction, or a vocal cord abnormality Bronchoscopy Rarely needed. It s main use is to exclude an obstructing airway tumor, e.g. carcinoid Lung biopsy is very oc casionally needed in those in whom no adequate explanation for persistent and minimally rev ersible air \202 ow obstruction is seen, to exclude another cause, e.g. bronchiolitis obl iterans Biomarkers Studies support the use of exhaled NO to determine optimum inhaled corti costeroid dose in moderate asthma. This may also be useful in diagnosis. Main differential diagnoses in asthma Consider especially if unusual features in the history, or poor correla- tion between objec tive measures and symptoms, or poor treatment response: \200 Upper airway obstruction (breathlessness, noisy, stridulous breathing, low peak \202 ows out of proportion to FEV1) Foreign body aspiration Tumor, especially tracheal (but can resp ond to steroids) CCF (young patient with a murmur) Vocal cord dysfunction Hyperventilation syndrome Chronic thromboembolic disease or primary pulmonary hypertension Interstitial lung disease Churg \200\223Strauss syndrome (and other eosinophilic lung diseases) Bronchioliti s (p 159) Gastro-oesophageal re \202 ux disease. \200 \200 \200 \200 \200 \200 \200 \200 \200 CHAPTER 18 Asthma 128 Acute severe asthma Most asthma deaths occur outside hospital and are: \200 \200 \200 In patients with chronic severe disease In those receiving inadequate medical treatment In those who have been symptomatically deteriorating and may have already sought medical help Associated with adverse behavioral and psychosocial factors. Fatality in asthma is due to cardiac arrest secondary to hypoxia and acidosis \200\224rever sal of hypoxia is paramount Give high \202 ow oxygen Risk factors for fatal or near fatal asthma \200 Previous near fatal asthma, e.g. previous ventilation or respiratory acidosis Three or more classes of asthma medication Repeated A&E attendances Large B2 agonist use Adverse psychos ocial features Brittle asthma. \200 \200 \200 \200 Brittle asthma \200\224appears to be a particular subtype or \200\230phenotype \200\231 \200 Type 1 \200\224wide PEF variability (>40% diurnal variation for >50% of the time over >150 days), despite appropriate therapy Type 2 \200\224sudden severe attacks on background of ap parently good control. Severity of acute asthma Moderate \200 \200 \200 \200 Increasing symptoms PEFR 50 \200\22375% predicted or best No features of acute severe asthm a One hour following treatment in A&E, patients with PEF >75% pre- dicted or best may be di scharged home with appropriate changes to their asthma medication in the absence of concern s, e.g. \200 \200 \200 \200 \200 \200 \200 \200 Signi \201 cant ongoing symptoms Compliance concerns Living alone Psychological problems o r learning dif \201 culties Previous near fatal or brittle asthma Nocturnal presentation P regnant Exacerbation despite adequate oral steroid pre-presentation. ACUTE SEVERE ASTHMA 129 Severe asthma De \201 ned as any of: \200 \200 \200 \200 PEFR 33 \200\22350% predicted or best RR >25 HR >110 Inability to complete sentence in one breath. Life-threatening asthma Any one of: \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 PEFR <33% SaO2 <92% (NB needs ABG) PaO2 <8 kPa Normal CO2 (4.6 \200\2236 kPa) Silent chest Cyanosis Poor respiratory effort Bradycardia/arrhythmia/hypotension Exhaustion Confusion Co ma. Near fatal asthma \200 \200 Raised PaCO2 and/or Needing mechanical ventilation with raised in \202 ation pressures. 22 Hospital treatment of acute asthma Airway \200\224ensure no upper airway obstruction Bre athing \200\224give high \202 ow oxygen Circulation \200\224gain IV access Monitoring \200 Record PEF on arrival in A&E, 15 \200\22330 min after starting treatment, and regularly the reafter according to response Record O2 saturation and maintain \211 92% ABG for pH and Pa CO2 if saturation <93% or other severe features Record and document heart rate and respirat ory rate Measure glucose and potassium Oxygen \200\224high concentration (40 \200\22360%) a nd high \202 ow mask, e.g. Hudson CXR to exclude infection/pneumothorax. \200 \200 \200 \200 NB CO2 retention following administration of high- \202 ow oxygen is not a problem in acut e asthma. A high CO2 indicates a life-threatening attack and should precipitate urgent ITU review for ventilatory support, not controlled oxygen therapy. CO2 is often low (due to hyp erventilation). A normal CO2 may indicate a tiring patient. 130 CHAPTER 18 Asthma 22 Hospital treatment of acute asthma (cont.) Treatment B2 agonist \200\224inhaled or nebul ized, e.g. nebulized salbutamol 2.5 \200\2235 mg, driven by oxygen. Give repeated doses, or continuous, e.g. 5 \200\22310 mg per hour. Use IV only if inhaled therapy cannot be used r eliably (rarely the case). NB risk of hypokalaemia with B2 agonist and steroids. Anticholin ergic \200\224nebulized ipratropium bromide added to B2 agonist therapy may improve broncho dilatation in acute severe asthma, if poor initial B2 agonist response. Steroids \200\224th e earlier given in an attack, the better the outcome. Oral is as effective as intravenous. Dose 40 \200\22350 mg oral prednisolone, continuing for at least 5 days or until recovery. There is no agreed de \201 nition of recovery, but sensible to con- tinue oral steroids un til peak \202 ow is maintained for 5 \200\2237 days. The dose can be stopped abruptly (as suming the patient continues on inhaled steroid). This does not apply to patients on repeat ed doses, or long-term steroids, where a longer course may be appropriate. Inhaled corticos teroids should be continued (or started as soon as possible) as part of the chronic disease management plan. IV magnesium sulfate \200\224immediately if very severe, and if poor response to above ther apies, 1.2 \200\2232 g IV infusion over 20 min. The safety and ef \201 - cacy of repeated doses has not been assessed. Recent data suggest nebulized magnesium may also be of bene \201 t, though must be adequately diluted. Further data are awaited. IV aminophylline \200\224some patients may respond, give if poor response to initial therap y, in acute severe or life-threatening disease. Dose 5 mg/kg loading dose over 20 min, foll owed by continuous infusion of 0.5 \200\2230.7 mg/kg (500 mg in 500 mL normal saline or 0.5 % dextrose at (0.5 x body weight in kg) mL/h). If on maintenance therapy, do not give loadi ng dose but start continuous infusion. NB Needs therapeutic drug monitoring. Side-effects: nausea, arrhyth- mias, palpitations. Antibiotics \200\224only if infective element to the exacerbation. Most exacer- bations are due to viruses, especially the common cold. C. pneumoniae and M. pneumoniae are also impli cated. IV \202 uids \200\224patients are often dehydrated. Hypokalaemia (due to B2 ago- n ists) must be corrected. IM adrenaline \200\224may be useful if near arrest, whilst waiting for ITU support. ITU referral Liaise with ITU early! Better to discuss early a patient who does not subsequently need ITU input, than to \201 nd you and your patient in dif- \201 culty, with no ITU bed. There is no evidence to support the use of NIV in the management of asthma. Hypercapnic respirat ory failure in acute severe asthma is an urgent indication for endotracheal intubation. HOSPITAL TREATMENT OF ACUTE ASTHMA 131 When to discuss with ITU \200 \200 \200 \200 \200 \200 \200 Worsening PEF despite treatment Worsening hypoxia Hypercapnia Falling pH Exhaustion/poor re spiratory effort Drowsiness/confusion Respiratory arrest. Discharge Consider discharge when: \200 Reduced B2 agonist dose \200 Off nebulized drug s and on inhalers \211 24 h \200 PEF \211 75% predicted or best \200 Minimal PEF diur nal variation \200 Appropriate education has been given. Prior to discharge consider \200 \200 \200 \200 \200 Reason for the exacerbation. Could it have been avoided? Check patient \200\231s self-manag ement plan/asthma action plan Check inhaler technique (p 686) Book an appointment with GP o r practice nurse for within 24 h Book chest clinic appointment. CHAPTER 18 Asthma 132 Chronic asthma: management Aim to minimize symptoms and prevent exacerbations, prevent the poten- tial consequences of longstanding airway in \202 ammation leading to airway remodel ing and chronic unresponsive airway obstruction, and improve quality of life. The emphasis should be on education, self-management, and personal asthma action plans. Aim for: \200 \200 \200 Minimal day and night symptoms No exacerbations Normal lung function and prevention of lung function decline with the development of \201 xed air \202 ow obstruction No limit to p hysical activity Minimum steroid dose. \200 Treatment is based on disease severity using a step up/step down approach, starting treatme nt at the level appropriate to disease severity, based on the history, spirometry, and medi cation usage. The main aims during out-patient review are: \200 Ensure the diagnosis is correct and that symptoms are due to asthma and not coexistent/alte rnative pathology (e.g. re \202 ux, hyperventilation syndrome, etc.) Aim for no symptoms/n ormal lung function on minimal treatment Ensure an action plan is in place for exacerbation s Identify patients at risk of an adverse outcome. \200 \200 Pharmacological management British Thoracic Society Guidelines for the Management of Asthma Step 1 \200\224mild intermittent asthma \200 \200 Short-acting B2 agonist Check compliance, inhaler technique (including Volumatic or other s pacer), and eliminate potential triggers 10 puffs per day (2 or more canisters/month) is a marker of poorly controlled disease. Step 2 \200\224regular preventer therapy \200 \200 \200 Start at 400 g/day beclomethasone (BDP) in a twice daily dose Titrate steroid dose to sym ptoms, aiming for lowest effective dose Local steroid side-effects only (oral candida, dysp honia) from BDP \211 800 g per day Possible dose-related bone density effects at this d ose or above Fluticasone (Flixotide ) provides equal clinical activity to budesonide (e.g. Polemicist ) at half dosage. Mometasone (Asmanex ) is a new inhaled steroid; the current limited evidence suggests it is equivalent to twice the dose of BDP. Ciclesonide (Alvesco ) is another new inhaled steroid. It is a pro-drug, and the available evidence suggests it may have fewer local oropharyngeal side effects and less systemic activity than convention al inhaled steroids. The clinical bene \201 t and ef \201 cacy to safety ratio data have not been fully established. \200 CHRONIC ASTHMA: MANAGEMENT 133 Qvar (beclomethaosne diproprionate) has a smaller particle size and may be of bene \201 t in some, 400 g bd is as effective as \202 uticasone 500 g bd Step 3 \200\224add on therapy \200 If taking 200 \200\223800 g/day inhaled steroid, consider long-acting B2 agonist. A combi nation preparation may be appropriate If there is no response to a LABA, stop it and increa se the inhaled steroid The combination of an inhaled corticosteroid and LABA is now license d as maintenance and reliever therapy, if a rapid onset LABA, e.g. formoterol (Oxis ) is u sed, in the context of a personal asthma action plan. It is not clear if this is superior t o more conventional doses of inhaled steroid and LABA. Step 4 \200\224Poor control on moderate dose inhaled steroid and add on therapy: addition o f fourth drug \200 Ensure de \201 nite bene \201 t is obtained from any of these subsequent drugs before con tinuing Leukotriene receptor antagonist \200\224about a third of patients respond. May be u seful if atopic or for exercise-induced asthma. Trial for 1 month and stop if there is no r esponse. Also indicated in allergic rhinitis \200\224so consider if this is present as well Theophylline (has side-effects, e.g. nausea, and needs therapeutic drug monitoring) Slow-r elease oral B2 agonist. Step 5 \200\224Continuous or frequent use of oral steroids \200 NB Risk of side-effects if on oral steroids for >3 months or 3 \200\2234 courses per year W arn patient of potential side-effects (hypertension, diabetes, cataracts, gastric erosions) and ask GP to monitor. Start osteoporosis prophylaxis with calcium and vitamin D, or a bis phosphonate. Document baseline bone densitometry in those receiving prednisolone for more t han 3 months (see p 678). See www.rcplondon.ac.uk Aim for the lowest possible dose steroid. CHAPTER 18 Asthma 134 Chronic asthma: additional treatment options Steroid-sparing drugs, e.g. methotrexate, oral gold, and ciclosporin \200\224may be useful if other treatments are unsuccessful. They may reduce long-term steroid requirements, but a ll have side-effects and need hematological surveillance. There are very few data to suppor t their use, and signi \201 cant variability in response. Guidelines suggest a 3-month tri al, once other drugs have proven unsuccessful, with treatment in a center with experience o f their use. Continuous subcutaneous terbutaline infusion via a portable syringe driver may be useful. Standard dose is 5 mg over 24 h, but up to 15 mg/24 h may be given. Use terbuta line nebulizer solution (2.5 mg/mL) e.g. for 10 mg/24 h, use 4 ml of nebulizer solution, wi th 6 ml of saline, infuse the 10 ml over 24 h. Bene \201 cial effects have been reported i n severe asthma, but safety and ef \201 cacy have not been assessed in RCTs. Best responde rs may be those with marked PEFR variability ( \200\230type 1 brittle asthmatics \200\231) to allow steroid reduction. Omalizumub Recombinant humanized monoclonal antibody against IgE has been shown to reduce e arly and late asthmatic responses after allergen challenge, and is now licensed for atopic individuals with dif \201 cult to control disease, in combination with other standard trea tments. The drug removes circulating and tissue IgE by promoting loss of high af \201 nity IgE receptors on mast cells, basophils, and dendritic cells, leading to reduced airway in \202 ammation. Compared with placebo, it has been shown to reduce exacerbation rates, with improvement in asthma symptoms and quality of life scores, but with no overall change in l ung function. Meta- analyzes suggest a reduction of around 100 g of inhaled corticosteroi d is achieved per day compared with placebo.