Further reading Light RW, Gary Lee YC (eds.). Textbook of Pleural Diseases, 2nd edn. London: Edward Arnold Publisher Ltd, 2008. Maskell NA, Butland RJA. BTS guidelines for the investigation of a unilateral pleural effusion in adults. Thorax 2003; 58(2): 8 \200\22317. Blood tests Essential initial blood tests that should be performed in all new patients pres enting with a pleural effusion are: \200 FBC & CRP \200\223 to identify possible underlying infection and allow monitoring of respo nse to treatment. Clotting screen \200\223 to allow correction of any abnormali- ties prio r to any invasive procedures. Liver function tests and calcium \200\223 often abnormal in malignancy. W MAN & M HIND 56 3.9 Unexplained respiratory failure The introduction of bedside ABG measurement and non- invasive ventilation has revolutionize d the management of respiratory failure in the acute setting. The history, exami- nation an d initial investigations of these patients usually points to a straightforward diagnosis an d subsequent man- agement plan. In this section we will highlight a clinical ap- proach to patients where the cause of respiratory failure is not obvious on initial assessment. Respi ratory failure is commonly classi \201 ed into 2 types de- pendent on the arterial partial pressure of carbon dioxide; type 1 \200\223 hypoxaemia (PaO2 < 8kPa) with a normal or low carbon dioxide, and type II \200\223 hypoxaemia and hypercapnoea (PaO2 < 8kPa, PaCO2 >6kP a). The underlying pathophysiol- ogy of these disorders is quite different. Type 1 respirat ory failure is due to an increased alveolar \200\223arterial (A \200\223a) gradi- ent with a normal or increased ventilatory response. This is a \201 nal common path for many disea ses not just those with lung pathology, e.g. left ventricular failure. Patients present- in g with type 2 respiratory failure or ventilatory failure can have a normal A \200\223a grad ient and it is these patients that we will consider below. A logical approach is to \201 rstly to exam- ine the causes of unexpected respiratory failure Airways obstruction/ Unrecognized COPD/ severe asthma mixed Obstructive sleep apnoea/obesit y/ muscle weakness History A careful and thorough history with clear timelines, par- ticularly for neuromuscul ar weakness, often points to a particular disorder. Sleep disturbance is often an early fea ture of many neuromuscular disorders and may predate breathlessness. Shoulder pain might su ggest neuralgic amyotrophy. Orthopnoea, breathlessness when bathing or swimming is suggesti ve of diaphragm weakness. Swal- lowing and speech dif \201 culties are important clues. Co llat- eral history from partners and/or family is important par- ticularly if the patient p resents with a reduced level of consciousness. Examination A full examination can reveal subtle diagnostic clues; the rate, depth and patt ern of breathing should be noted e.g. abnormal slowing of breathing seen in opiate use or C heyne \200\223Stokes periodic respiration seen in cerebral and cardiac disease; scars and e vidence of previous surgery might point to phrenic nerve injury; neurological signs such as fatigability, fasciculation, myotonia, and weakness should be looked for; abdominal parado x (inward drawing of the abdomen during inspiration) points to diaphragm weakness. Causes of unexplained respiratory failure Failure of ventilatory drive Neural suppression O piates Overdoses Metabolic alkalosis Polio/postpolio Brainstem stroke Arnold \200\223Chiari malfor mation Syringobulbia CNS infection (encephalitis, toxoplasmosis, tuberculoma) Brainstem tum or Brainstem disease Initial investigations ABGs \200 \200 \200 \200 Assessment of blood gasses off supplementary oxygen. The level of PaCO2. The base excess/ba se de \201 cit. A \200\223a gradient (normal <2.5 changes with age). Failure of the ventilatory pump Myopathies Chest radiograph/HRCT This may reveal evidence of unsuspected lung disease Acid maltase de \201 ciency Duchene muscular dystrophy Ulrich \200\231s muscular dystrophy Myotonic dystrophy Limb-girdle dystrophy In \202 ammatory myopathies Motor neuron disease Neuralgic amyotrophy Guillain \200\223Barr syndrome Spinal muscular atrophy (II-IV) Cord injury Myasthenia gravis Lambert \200\223Eaton syndrome Post-muscle relaxants e.g. suxamth onium Anti-cholinesterase poisoning (organophosphate poisoning) Critical care neuropathy/my opathy Obesity Scoliosis Thoracoplasty Flail chest Pneumothorax or large effusion Ankylosin g spodylitis Lung function \200 \200 \200 \200 \200 Unexpected airway obstruction. Reduction in vital capacity (chest wall or neurological). Fa ll in supine VC (diaphragm weakness). If supine VC <1 liter then this likely to be cause of failure. Mouth pressure, sniff pressures and trans-diaphragm pressures can be useful in sp eci \201 c situations. Neuropathy Other tests \200 Sleep study \200\223 to exclude REM related hypoxaemia, obstructive sleep apnoea. CK \200 \223 elevated in some myopathies. ANA, ANCA \200\223 repeated measurements are helpful in vasculitis. Acetyl cholinesterase receptor antibodies \200\223 myasthenia gravis. ECG \200\223 assessment of right and left heart function, esti- mation of pulmonary artery pres sure and exclusion of structural lesions is often helpful. Electromyography/nerve conductio n studies \200\223 diagnos- tic for MND, myotonia, myasthenia. Muscle biopsy \200\223 aci d maltase de \201 ciency. Neuromuscular junction \200 Mixed Chest wall abnormalities CHAPTER 3.9 Unexplained respiratory failure 57 Brainstem imaging \200\223 gadlinium-enhanced MRI to exclude to ventilate adequately unaided or clear bronchial secre- tions. Reversal of muscle relaxan t initially showed a good response but then ventilation deteriorated again. She remained in tubated and ventilated, and eventually re- quired a tracheostomy. There was a history from the daughter that the patient had been complaining of inter- mittent tiredness and muscle w eakness for several months before the operation. Electrophysiological studies showed a decr ement in compound muscle action potential ampli- tude on repetitive nerve stimulation (Fig. 3.9.2), whilst single \201 bre EMG demonstrated abnormal jitter. Histology from the medi astinal mass con \201 rmed a thymoma. Tensilon test demonstrated an immediate improvement in maximum inspiratory pressure measured via the tracheos- tomy from 18cmH2O to 65cmH2O. Se rologic testing con- \201 rmed autoantibodies to the acetylcholine receptor. The patient was started on pyridostigmine and underwent plas- mapheresis, followed by prednisolone. The patient was eventually decannulated, and managed without the need for non-invasive ventila tion. Diagnosis \200\223 myasthenia gravis. structural lesions CSF sampling \200\223 lumbar puncture to exclude CNS in \202 am- mation/infection Clinical cases Case 1 A 65-year-old man, following an elective left total hip replacement, was noted to have frequent oxygen desatura- tions in recovery. Daytime ABGs on room air dem onstrated a PaO2 8.5kPa and a PaCO2 6.8kPa. Chest radiograph was normal. Further questionin g of his wife revealed a several year history of heavy snoring, witnessed apnoeas, and unre freshing sleep. The patient also suffered from signi \201 - cant daytime hypersomnolence a nd had been involved in a car accident 4 months previously where he dozed off during drivin g and crossed the central reservation. Exami- nation revealed a BMI of 36 and a bull neck. Overnight oximetry is shown in Fig. 3.9.1. The patient was com- menced on CPAP therapy with good symptomatic effect, and at 3 months, ABGs on air revealed a PaO2 10.5kPa and a PaCO2 5.8kPa. Diagnosis \200\223 severe obstructive sleep apnoea. Case 2 A 33-year-old lady admitted from Accident & Emergency with a 2-week history of gener alized lethargy, culminat- ing in being bed-bound for 24 hours. 4 weeks prior to admission, she had a viral upper respiratory tract infection that was self-resolving. On examination she had a sym- metrical distal weakness of her lower limbs associated with lower limb are \202 exia. She developed progressive muscle weakness and a steady deterioration in limb fun ction on the general ward. She began complaining of breathlessness and dif \201 culty in c oughing, and vial capacity was measured at 900ml. ABGs demonstrated a pH 7.28, PaO2 9.4kPa and a PaCO2 8.0kPa. The patient was intubated and admitted to intensive care. Brain and lun g imaging revealed no abnormalities. CSF examination demonstrated normal cell count but ele vated protein level, and neurophysio- logy showed evidence of demyelination with signi \201 cant slowing of nerve conduction. The patient was treated with IV immunoglobulin, and made a progressive recovery and was eventually extubated. At 2 months, however, she still r equired nocturnal non-invasive ventilation due to moderate respiratory muscle weakness and nocturnal hypoventilation. Diagnosis \200\223 Guillain \200\223Barr syndrome. Fig. 3.9.2 Case 4 A 44-year-old man presented with a 4-month history of progressive shortness of breat h and reducing exercise tolerance. Symptoms were particularly worse on lying \202 at at n ight. He was a keen swimmer, but in the last 2 months, he had stopped going to the pool as he was get- ting breathless even standing in the deep end. In the previ- ous month, he was feeling muzzy-headed and getting fre- quent headaches in the morning. Examination revealed evidence of abdominal paradox and tongue fasiculations. Vital capacity dropped from 2.0 to 1.1 litres from sitting to supine positions. Sniff nasal pressure was markedly reduced at 2 2cm H2O (normal >70cm H2O). Chest radiograph demonstrated small lung volumes. ABGs on room air were PaO2 11.1kPa and a PaCO2 6.7kPa. Overnight sleep study showed REM related oxygen d esaturations (Fig. 3.9.3) and a rise in transcutaneous CO2 to above 9kPa. The patient was s tarted on domiciliary non-invasive venti- lation with good palliation of symptoms. EMG demo n- strated \201 brillations, positive sharp waves and fasciculation potentials. The patie nt subsequently developed signi \201 cant Case 3 A 68-year-old woman was admitted to the ICU following an elective mediastinoscopy an d biopsy of a mediastinal mass imaged incidentally on chest radiograph and subse- quent CT. Following general anesthesia, she was unable Fig. 3.9.1 W MAN & M HIND 58 Fig. 3.9.3 SaO2 Plot \200\223 oximetry data recorded over the entire night. Heart Plot \200\223 heart rate data recorded over the entire night Stage Plot \200\223 sleep stages r ecorded the entire night. bulbar symptoms, rapidly progressing to dysphonia, dysphagia and pooled secretions. Diagnos is \200\223 motor neuron disease. Clinical pointers \200 \200 Does the patient require immediate ventilatory support? Is the clinical setting appropriate for the patient e.g. gen- eral ward, level 2 (HDU) or level 3 (ICU) care? Is there an appr opriate ceiling of treatment? Does the patient require intubation and ventilation? \200 59 Chapter 4 Asthma Chapter contents 4.1 Pathophysiology 60 4.2 Allergic rhinitis 64 4.3 Pharmacology 68 4.4 As thma in pregnancy 76 4.5 Acute asthma 78 4.6 Chronic asthma management 82 D ROBINSON 60 4.1 Pathophysiology De \201 nition and epidemiology \200 AUTHOR \200\231S TIP On a practical clinical level patients may \201 nd it useful to conf irm sensitisation to pets or pollen allergens. Aspergillus sensitisation and screening for allergic bron- chopulmonary aspergilosis should form part of the work-up of all symptomatic asthmatics (skin test or RAST for speci \201 c IgE, blood (and/or sputum) eosinophil coun t, Aspergillus precipitins and CT if indicated by symptoms of chronic sputum production). Asthma is usually de \201 ned clinically as reversible air \202 ow limitation, but curren t de \201 nitions also recognize the presence of airway hyper-responsiveness to bronchoc- onstricting stimuli such as histamine, and eosinophilic airway in \202 ammation. It affect s 2.5 million children and 3 million adults in the UK. Around 70% of asthmatics are atopic (that is they make IgE responses to common allergens such as pollen, dust or animal danders ), and 30% non-atopic. Asthma may be triggered by occupational exposure, drugs (including a spirin: around 1%). Asthma attacks or exacerbations may be triggered by viral infections, a llergen exposure or non-speci \201 c irritants (see Acute asthma, p. 78). Genetic analysis of asthma has de \201 ned genes linked to atopy, airway hyper-responsiveness or asthma sy mptoms: including genes of the IgE receptor and genes associated with defective epithelial repair. Airway in \202 ammation in asthma \200 Patients who die of asthma show massive in \202 ammatory in \201 ltration of the airway a t post-mortem, often with marked eosinophilia and mucus plugging. The use of bronchial biop sies and induced sputum to sample the airways showed that epithelial shedding and airway eo sinophilia together with mast cell and lym- phocytic in \201 ltration are present even in mild or asymp- tomatic asthma. Exactly how in \202 ammation contributes to airway narrow- ing and AHR in asthma remains controversial although many of these features have been corre lated to disease severity measured by symptoms, air \202 ow obstruction or AHR. Bronchial biopsy is not helpful in diagnosis of asthma at present as generally changes are not speci \201 c. However, a \200\230normal \200\231 biopsy (no remodeling or in \202 ammation) ma y be helpful in apparent refractory asthma to focus on other causes for symptoms. Diagnosis \200 Asthma is diagnosed on the basis of variable symptoms of cough, wheeze, chest tightness and breathlessness and con \201 rmed by demonstration of reversible airway narrowing either s pontaneously over time or in response to inhaled 2 agonists. This can be documented as 15 % or more improvement in peak expiratory \202 ow rate or FEV1. Radiology may show hyper-i n \202 ation but is not useful in diagnosis except to rule out other conditions. AHR A characteristic feature of asthma is exaggerated narrow- ing of the airways in respons e to speci \201 c or non-speci \201 c stimuli, termed AHR. This can be measured in the lu ng function laboratory by controlled inhalation of agents such as histamine to determine th e dose of histamine causing a 20% fall in FEV1 from baseline (PD20). Such measurement is no t usually required for diagnosis but can be helpful if there is doubt. IgE and mast cells and basophils \200 A proportion of asthmatics are atopic and make IgE to common allergens. In these patients, allergen exposure may trigger attacks through cross linking high-af \201 nity IgE receptor s on mast cells and basophils leading to release of histamine, cytokines and growth factors from pre-stored sources in granules as well as de novo synthesis of leukotrienes and cytok ines. Histamine and lipid mediators may cause acute airway narrowing (within minutes) due t o oedema, vascular engorgement and muscle contraction and may be impor- tant in acute sever e asthma linked to anaphylaxis or some cases of \200\230brittle asthma \200\231. Cytokines and growth factors are thought to contribute to further airway in \202 ammation and airwa y remodeling (see below). These factors laid the basis for develop- ment of anti-IgE treatm ent for asthma (Xolair : see Key Issues: antibody therapy in asthma box): this antibody bl ocks the association of IgE with its receptor on mast cells and basophils. Of note IgE is a lso involved in \200\230anti- gen trapping \200\231 since dendritic cells have high af \201 nity IgE receptors which can act to \200\230catch \200\231 allergens for process- ing into peptides within the cell for subsequent presen- tation to and activation of T lymphoc ytes: anti-IgE also blocks this process. It is of note that non-atopic asthmatics also have increased IgE receptor-bearing cells in the airway, together with evi- dence of local airw ay synthesis of IgE and marginally raised serum IgE. Whether this is mechanistically impor- tant or a target for treatment remains unclear. Allergy and asthma \200 A majority of asthmatics are atopic and allergic and most have co-existent nasal airway dis ease. Treatment of rhinitis is important for symptom control and may in itself help with as thma control although direct evidence is scant. Assessment of allergy in asthma by skin pri ck testing and history is important if anti-IgE therapy is considered. Allergen avoidance m easures were ineffective in trials where they were applied broadly in house dust mite sen- sitised asthmatics. Further studies will be needed to determine whether focused interventio ns could be effective in severe asthmatics with predominant mono- sensitisation to house du st mites together with expo- sure in the home. Acute severe asthma associated with anaphyla xis may form type 1 \200\230brittle asthma \200\231, and should be investigated for allerg ic sensitisation. These rare patients may require injectable epinephrine (EpiPen ) to self -inject to treat attacks. CHAPTER 4.1 Pathophysiology 61 Eosinophils in asthma \200 T cells, cytokines, and asthma \200 Blood and sputum eosinophilia are characteristic but not diagnostic of asthma (atopic and n on-atopic). Eosinophils contain speci \201 c basic granule proteins which probably functio n in host defense against parasites and helminths, but which can also damage airway epithel ium in vitro and cause AHR if instilled into the airway of experimental animals. Eosinophil s can produce mediators such as leukotriene C4 which act to contract airway smooth muscle, recruit in \202 ammatory cells and increase mucus production. T lymphocytes are thought to be important drivers of airway in \202 ammation in asthma. Th ese cells are pivotal to speci \201 c immune responses and are activated by antigens proce ssed and presented by cells such as dendritic cells. In asthmatic airways, CD4+ T cells or helper T cells appear to be activated by allergens presented by den- dritic cells leading t o production of a particular pattern of messenger chemicals termed cytokines. These T-helpe r-2 (Th2) cytokines include interleukin (IL)-4 and IL-13 which turn on IgE antibody product ion and activate airway epithelium, and IL-5 which acts to recruit and retain eosinophils t o the airway. T cells producing these cytokines are the predominant cell type in asthmatic airways and strategies to block these cytokines with monoclonal antibodies or other therapi es have been developed, based on expression studies of human asthma and intervention studie s in animal models. Other cell types including mast cells and eosinophils and airway struct ural cells can also produce these cytokines so may amplify and perpetuate Th2 type in \202 ammation in asthma. More recently, cytokines that favor development of a Th2 type of respo nse have been described: these include IL-25 and IL-33 which act on the T cells and TSLP (t hymic stimulating lymphopoietin) which acts on dendritic cells. Clinical testing of anti-IL -4 and anti-IL-5 strategies was disappointing to date, whilst anti-IL-13 agents are cur- re ntly being evaluated. In addition other in \202 ammatory cytokines such as TNF and IL-6 ar e over-expressed in asthmatic airways: although anti-TNF therapies are useful in other in \202 am- matory pathologies such as rheumatoid arthritis and Crohn \200\231s disease, data in asthma is less compelling. Agents to target IL-25, IL-33 or TSLP may be of interest in t he future. Given these \201 ndings, together with studies that related air- way eosinophilia and gra nule proteins to asthma severity and results of animal models, the eosinophil hypothesis of asthma suggested that eosinophils were an important cause of much of the airway pathology of asthma. Certainly inhaled or oral steroid treatment dramatically reduces eosinophilic in \202 ammation in asthma. \200 However, more recent data has cast some doubt on the importance of eosinophils in asthma. A nti-IL-5 antibody treatment which dramatically reduced blood and sputum eosinophils failed to have clinical impact on asthma. Studies of a condition termed eosinophilic bronchitis (E B: associated with cough but normal lung function and no AHR), showed similar eosinophilic airway in \202 amma- tion in asthma and EB. The only difference detected between the two c onditions was in \201 ltration of airway smooth muscle with mast cells in asthma but not E B. It is important to note that these studies do not de \201 ni- tively rule out an import ant role for eosinophil in asthma. Eosinophils were not completely removed from the air- wa y by anti-IL-5 treatment (a 50% reduction was seen) and further studies are required to sho w whether eosi- nophil activation differs between EB and asthma. Eosinophils may play a rol e in asthma exacerbations. \200 In a study comparing use of sputum eosinophil measure- ment to usual guideline management o f asthma, the control of sputum eosinophilia more than halved exac- erbation rates. In the clinical anti-IL-5 studies, exacerbations rates were reduced (also 50% but not statisticall y signi \201 cant) at the highest anti-IL-5 dose. Some studies suggest persistent eosinoph ilia in a propor- tion (around 50%) of asthmatics who remain symptomatic despite inhaled st eroid and other treatment but that oth- ers have persistent symptoms with non-eosinophilic in \202 ammation. Whether there is a subgroup of asthmatics in whom analysis of airway eos inophilia will be incorpo- rated into management guidelines remains to be seen. KEY ISSUES: ANTIBODY THERAPY IN ASTHMA \200 Anti-IgE (Xolair ) is the only currently lic ensed anti- body therapy: data suggest it can reduce exacerbation rates by 50% and may redu ce steroid requirement. No effect on lung function in trials. It can only be used if total IgE is between 30 and 700IU/l. No clear guidance on how to assess response. Anti-IL-5: clin ical studies negative although trend to reduce exacerbation rates. Did not fully deplete ai rway eosinophils. Not licensed. Anti-TNF: one positive but at least 2 other negative trials in severe/moderate asthma. Not licensed. Others: anti-IL-4, anti-IL-13 receptor, anti-IL-5 receptor, antichemokines (eotaxin) either discouraging or no cur- rent data, but investiga ting may guide use to subgroups. KEY ISSUES: EOSINOPHILS IN ASTHMA \200 Eosinophilia is characteristic of asthma in blood, sputum and bronchial biopsies but is not diagnostic (also seen in some COPD and in eosinophilic bronchitis) Eosinophilia has been c orrelated with disease severity and these cells have the potential to contribute to epithel ial damage, AHR and in \202 ammation Animal models can reproduce features of asthma pathol - ogy by activating eosinophils in the airway and block AHR and remodeling by removing or r educing eosinophils Intervention studies with anti-IL-5 in humans were not effective clinic ally but did not fully deplete airway eosinophils or target eosinophilic patients Corticosteroids Corticosteroids are the main anti-in \202 ammatory agent in asthma and act in part through suppressing T-cell cytokine production. Other speci \201 c immunosuppress ive agents have been successful in trials including cyclosporin A and meth- otrexate, but h ave not found wide application in severe asthma and their use should be restricted to speci alist units in refractory asthma. D ROBINSON 62 factors to explain their persistent symptoms. Of note, asthmatics who smoke are less respon sive to inhaled ster- oids than non-smokers. However around 1% of severe asthmatics have as thma largely refractory to current treat- ment and there is a pressing need to evaluate the airway pathophysiology of these patients to define whether indeed there are different immu nopathological patterns (eosinophilic and non-eosinophilic disease or neutrophilic airway i n \202 ammation). Such studies should de \201 ne which patients will bene \201 t from ex pensive biological therapies of the present and future. Allergen immunotherapy Allergen immunotherapy has been used for many years to desensitize p atients with severe hay fever or anaphylaxis to bee or wasp venom. This treatment involves subcutaneous injection of escalating doses of allergen extracts which appears to induce imm une suppression or tolerance. This treatment has been shown to be effective for house dust mite-related asthma and is widely used in countries other than the UK. The limitation is th e risk of anaphylaxis: modi- \201 cation of the allergen for injection may allow more wid e- spread use of this therapy although at present it remains contraindicated for asthma in the UK. KEY ISSUES: DIFFICULT OR REFRACTORY ASTHMA \200 Regulatory T cells This arm of the immune system naturally suppresses immune responses and seems to prevent autoimmunity and immune-mediated organ damage due to over-exuber- ant immu ne responses to infection. There is increasing evi- dence that allergic diseases including asthma are associated with a relative failure of this arm of immunoregulation and strategie s to redress regulatory T cell function may be of interest. Systematic assessment protocols have identi \201 ed up to 15% non-asthma diagnosis and 30% non-adherence with treatment. Some evidence of \201 xed airway narrowing in a sub group. May be subtypes (eosinophilic and non-eosinophilic). Regional specialist \200\230dif \201 cult asthma \200\231 units may help in assessment. \200 \200 Anti-viral interferons Recent data also suggest that there may be reduced pro- duction of a nti-viral interferons in asthmatic airways: whether this predisposes to viral exacerbations of asthma or is amenable to therapy remains to be seen. AUTHOR S TIPS \200 Prednisolone and cortisol levels (sent to regional reference laboratory for HPLC) and trial of injected triamcinalone can be very helpful in assessing adher- ence and treatment respo nse. Full lung function tests are essential. Think of and exclude other diagnoses: just bec ause the notes have said \200\230asthma \200\231 for 20 years does not necessarily mean th is is correct! Nurse specialist and psychologist input is invaluable. Chemokines Recruitment of in \202 ammatory cells such as eosinophils and T cells depends i n part on production of chemoattractant cytokines (chemokines) by airway epithelial and oth er cells. Chemokine receptors are also co-factors for HIV infection, thus there is a huge p ush for development of agents to block these pathways. As yet such treatment has not been s tudied in human asthma. \200 Airway remodeling in asthma \200 Further reading Bousquet J, Rabe K, Humbert M, et al. Predicting and evaluating response to omalizumab in patients with severe allergic asthma. Respir Med 2007; 101: 1483 \200\223149 2. One of the characteristic histopathological \201 ndings in the asthmatic airways is epith elial change with increased goblet cells, increased airway collagen and extracellular matri x deposition and airway smooth muscle hypertrophy. These changes are referred to as \200 \230airway remodeling \200\231. Such changes are present even in children with asthma, and their relation to airway in \202 ammation and patho- physiology remains uncertain. Mathema tical modeling suggests that airway smooth-muscle changes may be important in airway hyper- responsiveness. It is also sug- gested that remodeling may predispose to \201 xed airway narrowing and the accelerated loss of lung volumes that occurs in asthma. Current therapies (including inhaled steroids) have little impact on airway remodeling and until reversal is achieved in animal or human studies the real impact of these changes will remain a subject of speculation. British Thoracic Society. Scottish Intercollegiate Guidelines Network. British guideline on the management of asthma. Thorax 2003; 58 (Suppl 1): 1 \200\22394. Busse WW, Lemanske RF Jr. Asthma. N Engl J Med 2001; 344: 350 \200\223362. Heaney LG, Robinson DS. Severe asthma treatment: need for char- acterising patients. Lancet 2005; 365: 974 \200\223976. Holgate ST, Davies DE, Powell RM, et al. Local genetic and environ- mental factors in asthm a disease pathogenesis: chronicity and persistence mechanisms. Eur Respir J 2007; 29: 793 \200\223803. O \200\231Byrne PM, Inman MD, Parameswaran K. The trials and tribula- tions of IL-5, eosino phils, and allergic asthma. J Allergy Clin Immunol 2001; 108: 503 \200\223508. Papadopoulos NG, Xepapadaki P, Mallia P, et al. Mechanisms of virus-induced asthma exacerba tions: state-of-the-ar t. A GA2LEN and InterAirways document. Allergy 2007; 62: 457 \200 \223470. Robinson DS. Regulation: the art of control? Regulatory T cells and Severe or \200\230refractory \200\231 asthma: the future challenge For most asthmatic pati ents, excellent disease control can be achieved with inhaled steroids, long acting bronchod ila- tors and or other agents as suggested by international guidelines. However, around 2% remain symptomatic despite treatment and these patients represent a major management challe nge as they account for 50% of resource use in asthma and are at increased risk of dying of asthma and of morbidity from their disease or oral steroid treat- ment. Thorough investiga tion is vital, as a substantial pro- portion have other chest disease, non-adherence or oth er asthma and allergy. Thorax 2004; 59: 640 \200\223643. Robinson DS, Hamid Q, Ying S, et al. Predominant TH2-like bron- choalveolar T-lymphocyte po pulation in atopic asthma. N Engl J Med 1992; 326: 298 \200\223304. CHAPTER 4.1 Pathophysiology 63 Mast cell Histamine Acute bronchospasm PGD2, LTCs Bronchial epithelium Eotaxin, PDG2 IgE Eosinophil Airway remodeling RBM Allergen Cytokines Chemokines Growth Factors B cell Fibroblasts IL-4 ? IL-5 IL-13 3 I L - 4 , I L - 1 Airway smooth muscle Fixed airway obstruction Chronic inflammation Airway hyper- responsiveness Th2 cell APC Fig. 4.1.1 Mechanisms in asthma. Allergen activates in \202 ammation through direct intera ction with IgE on mast cells and basophils but also via denritic cell processing and antige n presentation (APC) including activity of IL-25, IL-33 and TSLP, leading to activation of a Th2 response. Th2 cytokines IL-4 and IL-13 switch on IgE production andf activate the ast hmatic epithelium. Il-5 acts on eosinophil. These in \202 ammatory cells interact with str uctural cells including epithelium, smooth muscle and \201 broblasts to induce in \202 a mmatory cytokines and chemokines but also tissue remodeling though production and activatio n of growth factors such as TGF (transforming growth factors) which activate \201 brosi s. Together with goblet cell hyperplasia and smooth muscle cells hypertrophy and interactio n with mast cells these changes may contribute both to AHR and development of \201 xed ai rway narrowing. J UNSWORTH 64 4.2 Allergic rhinitis sensitivity (e.g. chlorine in swimming pools), are all com- mon examples of non-allergic rh initis. It is common for healthy individuals to \201 nd these factors irritant. Note how- ever, in any circumstance where the nasal mucosa is dam- aged (e.g. viral infection), thes e irritants will be more problematic. Infection (especially viral) is the commonest cause of rhini- tis overall, but this section focuses on allergic rhinitis. Background Pathogenesis Type 1 (IgE mediated) immediate hypersensitivity accounts for most allergic rhinitis. Typically, the allergic immune response is directed against airborne pro tein-based aller- gens. Local nasal in \202 ammation arises in the context of TH2 type imm une responses. Clinically, symptoms (sneezing, dripping, blockage) occur within minutes of exposure to trigger substances (allergens). ALLERGIC RHINITIS (UK) Seasonal Perennial Epidemiology The problem is seen worldwide. Prevalence has increased in the industrialized \200\230West \200\231. Around 20% of the UK popula- tion have allergic rhinitis. A familia l pattern of predisposi- tion is recognized, but the speci \201 c genetic factors have not been fully de \201 ned. Spring (tree) Summer (grass) Autumn (fungal) Work Domestic Dust mite Pets Fig. 4.2.1 Diagnostic algorithm. Rhinitis and asthma It is increasingly clear, that allergic rhinitis is a risk factor for a sthma. The supporting evidence includes: \200 KEY POINT Non-specific irritants do exacerbate true allergic rhinitis. Perennial rhinitis is an independent risk factor for asthma. Asthma is commoner in patients with perennial rhinitis, irrespective of whether they are atopic individuals. Children, wh o develop seasonal rhinitis, are more likely to develop asthma, but the risk is reduced if the seasonal allergic rhinitis is adequately treated. In patients with both asthma and rhin itis, there are fewer seasonal admissions for asthma, if the rhinitis is adequately treated . Bronchial hyper-reactivity increases in the hay fever season. One key clue is whether symptoms are all year round (per- ennial), seasonal, or perennial w ith seasonal exacerbation (e.g. house dust mite (HDM) with grass pollen sensitivity). Anoth er consideration is whether symptoms suggest a domestic- or work-related trigger. Work-rela ted symptoms (which may be due to true allergy or non-allergic irrita- tion) would reduce a t weekends and evenings typically, and be maximal towards the end of the working day. Examp les might include vets, bakers ( \202 our dust), latex (hospital staff), and chemicals / p aints. In the UK, seasonal allergic rhinitis may be due to \200 \200 \200 \200 Aspirin sensitivity/nasal polyps and asthma \200\230Samter \200\231s \200\231 triad. Rhini tis is often the \201 rst symptom. All non-steroidal anti-in \202 ammatories should be a voided. Nasal polyposis can be reduced medically (nasal corticos- teroid) or surgically. Ac cidental exposure to aspirin (or similar drugs) can provoke life-threatening adverse effect s. Clinical features can include urticaria, and angioedema, as well as asthma. Tree pollen: February \200\223May. Grass pollen: May \200\223August. Fungal spores: July \200\223September. Weed pollen: April \200\223September. Differential diagnosis Pointers against allergy include: \200 \200 Most seasonal rhinitis in the UK will be tree and or grass (weed and fungal spores are less of a problem) Asymmetric/unilateral symptoms/signs. Symptoms which fail to respond to adequate doses of c orticosteroid (see Treatment p.65). Mid-life onset with no previous allergic problems and n o family history of atopy. Diagnostic tests Skin prick tests These tests detect functional IgE speci \201 c antibody, in vivo. They are sensitive and at least for the common inhaled allergens (including HDM, pollens, pets) are reliable with sensitivity and specificity both approaching 80 \200\22390 %. Puri \201 ed allergen is applied externally to the patients skin, and the allergen is s cratched into the epidermis by gentle use of a sharp sterile blade. Positive results (itchy wheal and \202 are reactions) develop within 15 minutes, and the patient can leave the c linic knowing their results. This test has an extremely good safety record. Non-allergic diagnoses \200 \200 Congenital defects (e.g. ciliary dysmotility) \200\223 rare. Infection \200\223 common bu t typically acute/short lived, and with associated systemic features (malaise, fever, \200 \230 \202 u-like symptoms \200\231). Iatrogenic \200\223 medical (e.g. excessive deconges tant medi- cation). Iatrogenic \200\223 surgical. Autoimmune (Wegener \200\231s \200\223 rare). \200 Speci \201 c IgE blood tests Originally \200\230RAST \200\231 tests were performed. Nowad ays simpler non-radioactive assays are performed. Puri \201 ed allergen in vitro is used t o detect small amounts of Non-allergic irritation/in \202 ammation Cigarette smoke, pungent inhaled chemicals (e.g. perfumes), dusty environments (building sites), and chemical contact CHAPTER 4.2 Allergic rhinitis 65 allergen speci \201 c IgE. A sample of clotted blood (serum) is required by the laboratory , and results are routinely available the same day. Table 4.2.1 Topical medications Sneez Drip Blockage Total serum IgE This test is of little value. Elevated levels point to an allergic (atopic) tendency but elevated IgE per se does not prove allergic rhinitis. Results from skin prick tests and from allergen speci \201 c IgE blood tests largely agree with one another, and costs are comparable. Saline douches ++ Decongestant +++ Anti-histamine ++ + Ipatropium bromide +++ Topical corticosteroid +++ +++ +++ Chromoglycate ++ + + Provocation tests Allergen challenge, to determine if symptoms are reliably provoked is rar ely necessary, and in some circumstances (e.g. asthmatics) carries some risk. In the same way that many asthma suffers may not have been taught how to optimally use thei r inhalers, the major- ity of patients with allergic rhinitis do not employ the correct del ivery technique. A \200\230head down \200\231 position (with the head bent forward, akin t o kneeling on a prayer mat) helps ensure that medication does not simply drip into the oro- pharynx. Administration should be passive (no violent snif \201 ng). Systemic decongestant s are often less effective than topical equivalents and are best avoided. Both preparations risk rebound congestion if overused (more than 1 week). Ephedrine is the safest topical sy mpathomimetic, and can be effective within hours. Treatment Allergen avoidance This can be dif \201 cult or near impossible. Some situations are easier to manage than others \200\223 e.g. removing feather pillows from the home. KEY POINT Some pet epithelial allergens, (notoriously cat), can per- sist for many years af ter a cat has died or been removed, despite house cleaning. Mild rhinitis Often, the \201 rst step should be to try saline washouts and or topical de congestants (e.g. ephedrine). These sim- ple treatments with or without anti histamine (ant i-H1 receptor) topically or orally may be sufficient on an as required basis. Oral anti-his tamines have few side effects and are easier to administer than their topical counterparts. HDM \200\223 a very common culprit Typical features include: \200 \200 \200 Symptoms worst \201 rst thing in the morning. Tendency to wake with nasal obstruction. Sy mptoms with vacuum cleaning / dusting. KEY POINT HDM can be strangly limked to eczema and reduced exporure can lead to improvement of eczema in many cases. Moderately severe rhinitis For more severe symptoms, (see Table 4.2.1), topically administe red corticosteroid is the gold standard. Aim to use the lowest effective doses topically. C oncurrent anti- histamine will usually also be required. HDM reduction measures include: \200 Severe rhinitis Treatment options include addition of: \200 \200 Purchase of barrier bedding (pillow cases and sheets). HDM feeds on shed human epithelium, and large reser- voirs of HDM are found in bedding. Use of chemicals (acaricides), which ki ll HDM. Maintaining a domestic environment which is unfavour- able to HDM (increased ventil ation, low humidity, use of air \201 lters). Topical chromoglycate. Topical ipatropium bromide \200\223 very useful for vasomotor drip. Oral leukotriene antagonists (reduce obstruction/ dripping). \200 