Causes \200 Pharyngeal occlusion by tongue and other muscles, secondary to loss of muscle tone. This ma y be secondary to drugs, alcohol, a neurological event, or cardiorespiratory arrest Vomit o r blood Inhaled foreign body, which may also cause laryngeal spasm Laryngeal obstruction du e to oedema from burns, in \202 ammation, or anaphylaxis Excessive bronchial secretions, m ucosal oedema, bronchospasm: may cause airway obstruction below the larynx Infection, such as epiglottitis Any cause of chronic airway obstruction, such as an airway tumor or extrins ic compression due to tumor or lymphadenopathy, may dete- riorate precipitously. \200 \200 \200 ACUTE UPPER AIRWAY OBSTRUCTION 641 22 Management of upper airway obstruction Call for senior anesthetic help early \200 Open the airway with backwards head tilt, chin lift, and forward jaw thrust. In cases of tr auma, do not tilt the head, but perform a jaw thrust only If unsuccessful at restoring norm al respiration, visually inspect the mouth for obvious occlusion and remove it with a \201 nger sweep. Leave well- \201 tting dentures in place If there is a witnessed history of choking, consider performing the Heimlich maneuver to dislodge the particle ( \201 rm a nd rapid pressure applied beneath the diaphragm in an upwards movement), or directly visual ize the airway with a laryngoscope and use McGill \200\231s forceps to remove the particle, or with bronchoscope and the use of biopsy forceps If the patient is breathing, consider i nserting an airway to maintain patency: oropharyngeal (Guedel) or nasopharyngeal. Maintain oxy- genation, using mask with reservoir bag, delivering 10 \200\22315 L/min. If there is n o spontaneous respiratory effort, insert a laryngeal mask or endotracheal tube and deliver oxygen via self-in \202 ating bag with supplemental oxygen 10 L/min and reservoir bag. If they are not breathing and cannot be ventilated, a cricothyroidotomy may be necessary (p 76 3) Suction out secretions Maintain circulation with cardiac compression if necessary Seek d e \201 nitive treatment for the cause of airway obstruction, as appropriate. \200 \200 Heliox Helium \200\223oxygen mixtures can be used for patients with airway obstruction, oft en due to tumor compression or invasion. Helium has a lower density than nitrogen and can i mprove ventilation rapidly when used with oxygen. It can be used as an interim measure unti l more de \201 n- itive management is available, such as radiotherapy, or to allow time fo r radiotherapy to take effect. The evidence relating to its use is mainly case studies, wit h no randomized control trials. Nebulized adrenaline may also be helpful in upper airway ob struc- tion, especially laryngeal oedema. This is only a stabilizing measure to buy time un til de \201 nitive treatment is available. 642 CHAPTER 50 Upper airway diseases Anaphylaxis This is a potentially life-threatening medical emergency. Call for help Causes IgE-mediated type 1 hypersensitivity reaction to allergen. Histamine release causes the clinical syndrome. Typical allergens include bee or wasp sting, peanuts, \201 sh, dru gs, foods, latex, contrast media, muscle relaxants, anesthetic agents. Presentation Varying severity of: \200 \200 \200 \200 \200 \200 \200 \200 Angio-oedema Urticaria Dyspnoea Wheeze Stridor Hypotension Arrhythmias Also rhinitis, abdom inal pain, vomiting, diarrhea, sense of impending doom May have had previous episodes of se vere allergic-type reactions. 22 Management of anaphylaxis \200 \200 \200 Remove likely allergen Cardiopulmonary resuscitation if necessary Airway and breathing Admi nister high- \202 ow oxygen through non- rebreathe mask. If airway obstruction present, co nsider tracheal intu- bation. Airway swelling may make this dif \201 cult and cricothyroid otomy may need to be performed (see p 763) Circulation Give adrenaline (epinephrine) IM 1:1 000 solution 0.5 mL (500 g). Repeat after 5 min if no improvement or deterioration In tho se with profound shock and immediately life-threatening anaphylaxis, such as during anesthe sia, or those with no pulse. IV adrenaline can be given slowly, 100 g per min or 1 mL of 1:10 000 solution/min. Stop as soon as there is a response. This can be hazardous and needs cardiac monitoring IV \202 uids if hypotension persists: 1 \200\2232 L rapidly infused A ntihistamines, such as chlorphenamine 10 \200\22320 mg IV Consider steroids: 100 \200\22350 0 mg hydrocortisone IV Consider nebulized salbutamol or adrenaline if bronchospasm On disch arge, provide epipen (IM self-administered adrenaline) and advise on future episodes, Medic Alert bracelet, and card Consider immunology referral if allergen unknown. Consider C1 este rase inhibitor de \201 ciency, especially if repeated episodes. \200 \200 \200 \200 \200 ANAPHYLAXIS 643 Future developments Allergen immunotherapy aiming to desensi- tize to the allergen. Useful in those who cannot avoid allergen exposure. Small amounts of the allergen are injected usu ally weekly, with slowly increasing dose strengths until the maximum dose of the allergen i s admin- istered, which can take up to 12 months. Mechanism unknown, but probably related t o increased IgG binding to the allergen, falling allergen-speci \201 c IgE levels, and dec reased amount of circulating in \202 ammatory cytokines. Can protect against anaphylaxis f or 3 \200\2235 years, but \200\230top-up \200\231 doses necessary. Effective for dust, gra ss, tree, and weed pollen, mold spores, latex, and insect venom, as well as some animal all ergens. Side-effects of administra- tion: anaphylaxis, bronchoconstriction, local reaction. Some centers may not perform in people with chronic asthma because of the risk of death. Further information Abramson M, Puy R et al. Allergen immunotherapy for asthma. Cochrane Da tabase Syst Rev 2003; 4: CD001186 Advanced Life Support Provider Manual, 5th edn, 2006. Resuscitation Council UK 644 CHAPTER 50 Upper airway diseases Upper respiratory tract infections 1 Acute upper respiratory tract infections (URTIs) inclu de rhinitis, pharyn- gitis, tonsillitis, and sinusitis. Upper respiratory tract infections are the commonest cause of people taking time off work i n the United Kingdom. The majority are managed by general practitioners and will not reach a respiratory specialist. They are usually self-limiting and often do not require speci \201 c treatment. Acute rhinitis Nasal congestion with rhinorrhea, mild malaise, and sneezi ng. Most commonly due to viral infection (the common cold). Topical decongestants may be useful. There is no evidence for the use of antibiotics or antihistamines. Candidiasis Oral candida infection is common in those who ha ve received antibiotics, are immunosuppressed, or on oral or inhaled steroids. Seen as whit e plaque-like lesions on the tongue and pharyngeal mucosa. Treat with oral nystatin or amph otericin lozenges, and with oral hygiene. Severe infection can be debilitating, leading to dif \201 culties with eating, espe- cially in the elderly. Exclude underlying immunocompro mise (e.g. HIV, leu- kaemia) in those with persisting infection despite treatment. Acute ep iglottitis (supraglottitis) is infection mainly localized to the epiglottis and surrounding supraglottic structures. It is commoner in children than adults, but a mortality of up to 7% is reported in adults. This is due to upper airways obstruction from grossly oedematous upper airway tissue. \200 Haemophilus in \202 uenza, Streptococci, and Staphylococci are causative organisms Acute e piglottitis typically presents with a sore throat and dysphagia. Inspiratory stridor is les s common, but it can also present with acute upper airway obstruction and CXR in \201 ltra tes consistent with pulmo- nary oedema (due to high negative intrathoracic pressure) May ne ed airway protection with an endotracheal tube or tracheos- tomy: liaise with ENT/anestheti c colleagues early In severe infection, epiglottic swabs may be of diagnostic use, but bewa re of precipitating airway obstruction. Treat with third-generation cephalosporin for 2 wee ks (to cover B-lactam producing H. in \202 uenzae). Change to amoxicillin if sensitive Sinusitis The sinuses are normally sterile. The paranasal sinuses com- municate with the no se, and are therefore susceptible to infection from this route. All the sinuses drain by me ans of the mucociliary escalator. Blockage of free sinus drainage is a predisposing factor for bacterial infec- tion. Sinusitis is a common cause of persistent cough (see p 18 ). Den tal sepsis may lead to maxillary sinusitis, by direct spread. Acute sinusitis complicates 1 in 200 upper respiratory tract infections and usually presents with fever, nasal congestio n/discharge, and sinus pain which is worse on leaning forward. It may be associated with sy stemic upset. Respiratory viral infection interrupts normal defenses of the mucosal lining, producing mucous exudates, with secondary bacterial infection. S. pneumoniae and H. in \202 uenzae are the commonest pathogens. S. aureus and S. pyogenes are also causes, with Ps eudomonas in cystic \201 brosis. UPPER RESPIRATORY TRACT INFECTIONS 1 645 Mixed infections with anaerobes are seen in 10%. Speci \201 c diagnostic tests are not usu ally needed. If symptoms persist, antibiotic treatment may be indicated. Chronic sinusitis by de \201 nition, if present for >3 months. The ciliated epi- thelial sinus lining is rep laced by thickened strati \201 ed squamous lining, with absent cilia, due to repeated infe ction. Anaerobic infection is more common. Fungal infection is more common in atopic people with nasal polyps. Sinus mycetoma is a rare complication in neutropenic patients, dia- bet ics, and the immunocompromised. Presents with frontal headache (frontal sinusitis), maxillary pain, pain over bridge of nos e (ethmoidal sinusitis), retro-orbital headache (sphenoidal sinusitis), with purulent nasal discharge and blockage. Wegener \200\231s granulo- matosis may mimic the symptoms of sinus itis. Investigations are not usually warranted, but a sinus radiograph may show an air- \202 uid level, with thickened mucosal lining, or sinus opaci \201 ca- tion. CT is more sensitive, but not usually warranted unless surgical inter- vention planned or malignant disease susp ected. Treatment Analgesia, topical decongestants, antibiotics if severe infec- tion (amoxicillin \201 rst line, trimethoprim if penicillin allergic). Surgery may be warranted if prolonged infection, anatomical abnormality, or other complicat ions, e.g. if infection has spread to the cranial cavity or orbit. Spreading infection is u ncommon if there has been prior antibiotic treatment. 646 CHAPTER 50 Upper airway diseases Upper respiratory tract infections 2 Acute pharyngitis and tonsillitis 80 \200\22390% are c aused by viruses, most commonly adenoviruses, coronaviruses, rhinoviruses, and in \202 uen za viruses. Group B streptococci, Streptococcus pneumoniae, and Haemophilus in \202 uenzae may cause secondary infection. Mycoplasma and chlamydia are seen less commonly. \200 Pharyngitis and tonsillitis present with a sore throat, which is usually self-limiting. May be associated with fever, malaise, lymphadenopathy, conjunctivitis, headache, nausea, and vomiting Infectious mononucleosis (Epstein Barr Virus) is associated with phar- yngitis in 80% of cases. Diagnose with Paul Bunnell test for heterophil antibodies, and atypical monon uclear cells in peripheral blood Coxsackie A and herpes simplex cause \200\230herpangina s yndrome \200\231 \200\224ulcer- ating vesicles on the tonsils and palate CMV can also cause pharyngitis associated with lymphadenopathy and splenomegaly Lemierre \200\231s syndrome ( jugular vein suppurative thrombophlebitis) is a rare anaerobic pharyngeal infection (see p 446). Other causative agents \200 Corynebacterium diptheriae in unvaccinated populations. A pharyngeal membrane may form, wit h systemic symptoms, and \200\230bull neck \200\231 due to cervical lymphadenopathy. Low-g rade fever, with a relatively high pulse rate. Treat urgently with diphtheria antitoxin Vin cent \200\231s angina is anaerobic infection in those with poor mouth hygiene. Caused by Gr am-negative Borrelia vincenti and other anaerobic infections. Treat with penicillin Group A streptococcus may cause a more unpleasant illness, with sys- temic upset and dysphagia due to pharyngotonsillar oedema. Treatment is usually supportive, but anti-streptococcal antibiotics may be warranted if the re is severe infection. There is no evidence that antibiotics reduce the duration of sympto ms, but they may reduce complications (e.g. sinusitis, quinsy, and rheumatic fever, which i s rare in the Western world). Oral penicillin is the \201 rst-line treatment (or a macrol ide if peni- cillin allergic). Amoxycillin can cause a rash in infectious mononucleosis and so should be avoided. Throat swabs for group A streptococcus may be helpful in directing t reatment. Complications of untreated infection include peritonsillar abscess (quinsy), retr opharyngeal abscess, and cervical abscess. Treat with appropriate anti- biotics. Surgical d rainage is occasionally required. UPPER RESPIRATORY TRACT INFECTIONS 2 647 Laryngitis This is usually part of a generalized upper respiratory tract infection. Moraxel la catarrhalis is the causative agent in up to 50%. It may cause a hoarse voice or aphonia. Other causes include inhaled steroids, occupational exposure to inhaled chemicals, and gas tro-oesophageal re \202 ux disease. If a hoarse voice persists in a smoker, a laryngeal or lung cancer (with recurrent laryngeal nerve involvement) must be excluded. Other causes in clude tuberculous infection, HSV, CMV, diphtheria, fungal infections, and actinomycoses. Tr eatment Usually no speci \201 c treatment is required, as the illness is typi- cally self- limiting. Acute bronchitis, tracheitis, and tracheobronchitis In \202 ammation due to infe ction can occur in any part of the tracheobronchial tree, and is termed tracheitis, tracheo bronchitis, or bronchitis depending on the ana- tomical site. It usually follows viral infe ction, especially of the common cold type, and is commoner during in \202 uenza epidemics. Secondary bacte- rial infection is common, with H. in \202 uenza and S. pneumoniae common est. There is increased prevalence in the winter months. Presents with a productive cough, small volume streaky haemoptysis, and fever. Breathlessness and hypoxia are uncommon unless there is coexistent cardiorespiratory disease, or a concomitant pneumonia. Retrosternal ch est pain is common in tracheitis. Examination is often normal. Diagnosis is usually on the basis of the history. A persisting cough, espe- cially in a smoker, may warrant further inv estigation. Treatment is usually symptomatic, particularly in the previously well. Use anti biotics for persistent cough productive of mucopurulent sputum, or if there is coexistent c ardiopulmonary disease. This page intentionally left blank 649 Chapter 51 Vasculitis and the lung Classi \201 cation 650 Wegener \200\231s granulomatosis: presentation and diagnosis 652 We gener \200\231s granulomatosis: management 654 Microscopic polyangiitis 656 Goodpasture \200\231s disease 658 Churg \200\223Strauss syndrome 660 Rare pulmonary vasculitides 662 CHAPTER 51 Vasculitis and the lung 650 Classi \201 cation These are rare conditions, but are often seen in the specialist chest c linic (see p 25 for an approach to diffuse alveolar hemorrhage). Clinical fea- tures can be non-speci \201 c and similar to those seen in other diseases and diagnosis can therefore be dif \201 cult. Vasculitides are great \200\230mimickers \200\231 of other diseases, su ch as lung cancer or ARDS, and have a high untreated mortality. There is considerable overl ap between the different vasculitides, which can make de \201 nitive diagnosis dif \201 c ult. Suspect a diagnosis of vascu- litis if: \200 \200 \200 \200 Weight loss Low-grade fever Raised in \202 ammatory markers Chest disease is not improving or responding to treatment as expected: \200 \200 \200 \200 \200 \200 \200 \200 Associated renal impairment or positive urine dip for blood or protein Raised autoant ibodies No other clear diagnosis Unexplained dyspnoea Hypoxia Unexplained desaturation on exercise Haemoptysis Sinus or nasa l disease Wheeze CXR abnormalities/in \201 ltrates Abnormal KCO \200 \200 The primary pathology in vasculitis is in \202 ammation and necrosis of dif- fering sized blood vessels. The pulmonary vessels are involved as part of a multi-systemic vasculitis pr ocess. Small vessel vasculitides are the most common to involve the lung. Arterioles, capil laries, and venules located within the lung interstitium are affected. Neutrophil in \201 ltration and subsequent \201 brinoid necrosis causes vessel wall destruction. Necrotizing pulmonary capillaritis can also occur: characterized by a marked neutrophilic in \201 ltr ation of the interstitium. Interstitial capillaries become damaged, allowing red blood cell s to enter the alveolus; thus alveolar hemorrhage is a feature of many of the small vessel vasculitides. Further information Schwarz M, Brown K. Small vessel vasculitis of the lung. Rare diseases 10, Thorax 2000; 55: 502 \200\22310 CLASSIFICATION 651 Table 51.1 Classi \201 cation of vasculitis, based on the Chapel Hill International Consen sus, 1992 Primary vasculitis Lung involvement ANCA Small vessel Wegener \200\231s granulomatosis Frequent c-ANCA in 75%, p-ANCA in 15% p-ANCA in 70% c/p-ANCA p-ANCA in 10 \200\22320% Churg \200\223Strauss Microscopic polyangiitis Goodpasture \200\231s disease Frequent Frequent Frequent Medium size vessel Polyarteritis nodosa Rare Negative Large vessel Giant cell arteritis Rare Negative Takayasu arteritis Frequent Negative ANCA Anti-neutrophil cytoplasmic antibodies react with cytoplasmic granule enzymes in neutrophil s and stain them in one of two ways: \200 \200 Diffusely cytoplasmic pattern or c-ANCA Perinuclear pattern or p-ANCA These autoantibodies may have a direct role in pathogenesis as well as being disease marker s. ANCA have 2 major speci \201 cities: \200 Antiproteinase 3 antibodies (anti-PR3) \200\224associated with c-ANCA pattern Antimyelopero xidase antibodies (anti-MPO) \200\224associated with p-ANCA pattern. c-ANCA (anti-PR3) targets proteinase 3 and may suggest Wegener \200\231s granulomatosis (75 % of cases are c-ANCA positive). Levels correlate with disease activity and extent. Also fo und in patients with microscopic polyangiitis (45% of those with clinical disease will be c -ANCA positive). p-ANCA (anti-MPO) targets myeloperoxidase and has a wider range of disease associations, including other vasculitides and autoimmune dis- eases, HIV, lung cancer, pu lmonary \201 brosis, and pulmonary emboli. Further information Bosch X et al. ANCA. Lancet 2006; 368: 404 \200\22318 CHAPTER 51 Vasculitis and the lung 652 Wegener \200\231s granulomatosis: presentation and diagnosis De \201 nition and epidemiolo gy Necrotizing vasculitis affecting small and medium size vessels, especially in the upper and lower respiratory tract and also the kidneys. Associated granulomata. \200 \200 \200 \200 Unknown cause Male = female 3/100 000, 80 \200\22397% Caucasian Any age, but most common be tween 40 and 55 years Clinical features \200 ENT In 90%, upper airways involvement will be the \201 rst presenting sign. Nasal congest ion and epistaxis, with in \202 amed crusty ulcerated nasal mucosa. Nasal septum perforati on. Late sign is a saddle nose deformity. Sinusitis is common and may be painful. Otitis me dia. Subglottic ste- nosis, causing upper airway obstruction, dyspnoea, voice change, and c ough. Abnormal \202 ow \200\223volume loops Lung Affected in 85 \200\22390% of patients. Haemoptysis, cough, dyspnoea. Pleuritic chest pain Kidney Affected in 77% of patients. Haem aturia, proteinuria, and red cell casts. Only 10% have renal impairment initially, but 80% will have involvement during their disease course. Characteristic progressive deterioration of renal function Systemic Fever and weight loss Other organ systems (skin, eyes, joints, CNS) Vasculitic skin rash with granulomatous involvement in 46%. Muscle and joint pains. Co njunctivitis, scleritis, proptosis, eye pain, visual loss. Mononeuritis multiplex and CNS d isease. \200 Investigations Consider: \200 CXR Flitting cavitating pulmonary nodules, consolidation, or pulmonary in \201 ltrates, al veolar hemorrhage, parenchymal distortion, large and small airway disease, pleural effusion , bronchiectasis. Can look like neo- plasms, infection, or \202 uid overload HRCT of ches t Oxygen saturations FBC, U&E, CRP, ESR Serum ANCA, especially c-ANCA, is sensitive and fai rly speci \201 c. Present in 90% of patients with extensive Wegener \200\231s and 75% with limited. p- ANCA positive in 5 \200\22310% of patients with Wegener \200\231s. Combining i ndirect immuno \202 uorescence with speci \201 c immunoassays for antibodies to PR3 and M PO increases sensitivity and speci \201 city for Wegner \200\231s and micro- scopic polyan giitis to over 90%. Remember ANCA can be negative, especially in disease con \201 ned to t he respiratory tract. ANCA titres rise prior to a relapse and are higher when disease is ac tive, and this can act as a guide to starting treatment. However, high ANCA levels in the a bsence of clinical symptoms or signs may not represent active disease, \200 \200 \200 WEGENER \200\231S GRANULOMATOSIS: PRESENTATION AND DIAGNOSIS 653 and therefore ANCA levels should not be used in isolation to deter- mine treatment. Conside r CRP ESR also Urine dipstick and microscopy Red cell casts Pulmonary function tests, in cluding kCO Image sinuses Bony destruction makes Wegener \200\231s likely Bronchoscopy May show in \202 ammation and ulceration of larynx, trachea, and bronchi. Scarring and stenosi s may be seen. BAL is neutrophilic, also with eosinophils and lymphocytes. Transbronchial b iopsy is unlikely to be diagnostic Biopsy \200 \200 \200 \200 Respiratory tract and nose \200\224granulomata in association with medium and small vessel necrotizing vasculitis and surrounding in \202 ammation. Nasal biopsies are often non-spec i \201 c and may not be diagnostic Renal biopsy \200\224focal segmental or diffuse necroti zing glomerulo- nephritis. Pauci-immune and granulomata rare. Not speci \201 c for Wegener \200\231s Skin biopsy \200\224leucocytoclastic vasculitis granulomata Diagnosis Biopsy and ANCA are key to diagnosis. Biopsy whichever site is affected. May be n asal, lung (open or thoracoscopic), skin, or renal. If there is evidence on urine dip of re nal vasculitis, this may be the best and easiest biopsy site. Disease may be patchy in natu re, requiring repeat biopsies if the \201 rst is negative. High c-ANCA and anti-proteinas e 3 (PR3) is highly suggestive of Wegener \200\231s. Differential diagnosis of Wegener \200\231s granulomatosis Malignancy, TB, sarcoidosis, all ergic bronchopulmonary aspergillosis, Goodpasture \200\231s disease (anti-glomerular baseme nt membrane disease with pulmonary hemorrhage and nephritis), SLE, microscopic polyangiitis , con- nective tissue disease. CHAPTER 51 Vasculitis and the lung 654 Wegener \200\231s granulomatosis: management Involve the renal team and share care of the p atient. See p 675 for immuno- suppressive drug details. \200 Standard regimen for generalized or organ-threatening disease (e.g. active/progressive pulm onary or renal disease or CNS disease): \200 Induce remission with oral prednisolone (1 m g/kg/day, tapering weekly to a dose of 15 mg or less daily by 3 months) and cyclophos- pham ide orally (2 mg/kg/day, up to 200 mg/day) or IV (pulses at 2- or 3-week intervals, 15 mg/k g) for 3 \200\2236 months. Reduce cyclophospha- mide dose in elderly (e.g. reduce oral dose by 25% if >60 years, and by 50% if over 75 years) and in setting of renal impairment. Tape r cyclophosphamide dose to maintain WCC>4 \227 109/L and neutro- phils >2 \227 109, to re duce infection risk (see p 679 for more detail) The aim is to prevent irreversible tissue n ecrosis. There is evidence that this regime induces remission in 80% of patients at 3 month s and 90% at 6 months After induction of remission (at 3 \200\2236 months), consider switch from cyclophosphamide and prednisolone to maintenance therapy with prednisolone and either azathioprine (2 mg/kg/day for 12 months, then reduce to 1.5 mg/kg/day; check TPMT levels, p 678 ) or metho- trexate (15 mg once/week, increase to maximum of 20 \200\22325 mg once/ w eek by week 12; p 680 ). This avoids the morbidity associated with long-term cyclophosphami de use. Both azathioprine and metho- trexate have been demonstrated to maintain remission, although the evidence favors use of azathioprine Restart the regime if the patient relapses \200\224this may occur in 50% For severe life-threatening disease (e.g. rapidly progressive renal failure or massive pulm onary hemorrhage): \200 Plasma exchange/plasmapheresis (7 x 4 L exchanges over 2 weeks) has been shown to be more e ffective than methylprednisolone in the treatment of Wegener \200\231s granulomatosis. In p atients with severe pulmonary hemorrhage it is also effective and can be given along with f resh frozen plasma In addition, treat with pulsed methylprednisolone (500 \200\2231000 mg/d ay depending on body weight for 3 days) and intravenous cyclophos- phamide (15 mg/kg, reduc e if elderly or renal impairment) Dialysis for renal failure After induction of remission ( over 3 \200\2236 months), switch from cyclo- phosphamide to azathioprine or methotrexate wi th prednisolone as maintenance therapy \200 For localized disease or early systemic disease (without threatened organ involvement): \200 Prednisolone with either methotrexate or oral/pulsed cyclophos- phamide. Use of methotrexat e avoids cyclophosphamide-related toxicity, but may be associated with a higher relapse rat e. Localized disease may still be serious (e.g. retro-orbital involvement), and in these si tuations cyclophosphamide should be considered. WEGENER \200\231S GRANULOMATOSIS: MANAGEMENT 655 Duration of treatment Maintenance therapy is recommended to con- tinue for at least 24 mont hs after initial disease remission, as relapses are common. Some recommend continuing treat ment for up to 5 years, particularly if the ANCA remains positive PCP prophylaxis with co-t rimoxazole is recommended (960 mg 3 \227/week) in patients receiving cyclophosphamide and p rednisolone. There is some evidence that co-trimoxazole alone may be effective in the treat ment of especially limited Wegener \200\231s, although the reasons for this are not clear \200\224it may be due to suppression of nasal Staphylococcus aureus carriage, the presence of which is associated with an increased risk of relapse Osteoporosis prophylaxis should be considered Follow-up monthly for 3 months, then 3 \200\2236 monthly. Monitor FBC, U&E, CRP , LFT, ANCA, CXR, and kCO. Rising ANCA titres are a poor predictor of relapse; in the absen ce of other features of a relapse, follow up more closely, but do not increase immunosuppre ssion solely on this basis. Withdrawal of immunosuppression in the setting of a persistentl y positive ANCA is associated with relapse, however Relapses Treat minor relapses with an i ncrease in the prednisolone dose. Treat major relapses with cyclophosphamide and increasing prednisolone; consider IV methyprednisolone, plasma exchange Refractory disease Liaise wit h specialist; consider alternative therapies such as in \202 iximab, high-dose IV immunogl obulin, rituximab, anti-thymocyte globulin, or CAMPATH 1H (alemtuzumab, anti-CD52). Mycophe nolate or le \202 unomide are alternatives to azathioprine or methotrexate. Exclude underl ying infection, malignancy, and non-compliance \200 Prognosis Limited disease with pulmonary but no renal involvement and an often negative c-A NCA test has a better prognosis. However, this can progress over time to extensive disease, with classical destructive sinusitis, nephritis, and vasculitis and strong c-ANCA positivi ty, and is associated with higher mortality. Untreated, 80% of people with extensive Wegene r \200\231s will die in 1 year. Overall, 75 \200\22390% of patients can be brought into rem ission with treatment, although 50% relapse in 5 years and long-term follow-up is required. CHAPTER 51 Vasculitis and the lung 656 Microscopic polyangiitis At least as common as Wegener \200\231s and may be hard to disting uish. Managed in the same way. \200 \200 Incidence Male = female, mean age 50, mainly Caucasians Kidneys Main organ affected by a sm all vessel necrotizing vasculitis, causing proteinuria, and haematuria. Renal biopsy shows focal seg- mental glomerulonephritis with \201 brinoid necrosis and sparse immune deposit s Pulmonary involvement occurs in 30 \200\22350% of patients, with pleurisy, asthma, haemop tysis, and pulmonary hemorrhage. CXR may be sug- gestive of pulmonary hemorrhage p-ANCA pos itive, often c-ANCA also. Treatment with immunosuppression: steroids and cyclophosphamide (see previous page). Future developments It had been thought that anti TNFA agents were likely to have a role in acute vasculitis and seemed to work best in granulomatous disease. A randomized controlled trial of etanercept plus standard therapy for Wegener \200\231s granulomatosis showed no s igni \201 cant effect on remission rates (NEJM 2005; 352: 351 \200\22361). Further studies are ongoing of other anti- TNF agents. B-cell depletion with the monoclonal anti-CD20 antibody rituximab. This is used for non-Hod gkin \200\231s lymphoma, SLE, rheumatoid arthritis. Encouraging results in small studies of ANCA positive vasculitis, but no RCT as yet. Mycophenolate for immunosupression in vasculitis to induce remission. Used post-transplant. A large study vs. azathioprine is underway. Further information Lapraik C et al. British Society of Rheumatology and British Heath Prof essionals in Rheumatology guidelines for the management of adults with ANCA associated vasc ulitis. Rheumatology 2007; 46: 1615 \200\22316 Langford C, Hoffman G. Wegener \200\231s granulomatosis. Rare diseases 3, Thorax 1999; 54: 629 \200\22363 Frankel SK et al. Update in the diagnosis and management of pulmonary vasculitis. Chest 200 6; 129: 452 \200\22365 This page intentionally left blank CHAPTER 51 Vasculitis and the lung 658 Goodpasture \200\231s disease De \201 nition and epidemiology Linear deposition of IgG on the base- ment membranes of alveoli and glomeruli, which damages collagen and in the lungs allows leakage of blood. \200 \200 \200 \200 \200 \200 \200 Anti-glomerular basement membrane antibodies are detectable in blood Alveolar hemorrhage an d glomerulonephritis Important differential diagnosis of pulmonary \200\223renal syndrome A nnual incidence of 1 case per million Male:female = 4:1 Commonest age 20 \200\22330 years S econd peak when women in their late 60s are affected by glomerulo- nephritis alone Cause un known. Often a preceding viral infection. Smokers at greater risk of pulmonary hemorrhage, but not of Goodpasture \200\231s disease HLA DR2 association in 60 \200\22370%. Clinical features \200 \200 \200 Haemoptysis in 80 \200\22390% \200\224more common in smokers Cough, dyspnoea, fatigue, and weakness Examination: inspiratory crackles common. Investigations \200 \200 \200 Serum electrolytes show impaired renal function and often renal failure FBC Iron de \201 c iency anemia Urine dip and microscopy Haematuria, proteinuria, granular and typi- cally red blood cell casts. Occasionally macroscopic haematuria Anti-GBM and autoantibody screen CXR CT Diffuse bilateral patchy air space shadowing in mid and lower zones. May see air bro nchograms PFTs Restrictive defect with raised kCO if alveolar hemorrhage present. \200 Diagnosis Renal biopsy usually shows diffuse crescentic glomerulo- nephritis. Linear IgG de position detected by immuno \202 uorescence or immunoperoxidase. Lung biopsy shows active intra-alveolar hemorrhage with collections of haemosiderin laden macrophages. These are not speci \201 c changes, but may also show linear immuno \202 uorescence staining of IgG. D ifferential diagnosis Wegener \200\231s granulomatosis, other pulmonary renal syndromes. Management \200 \200 Involve the renal team and share care of the patient Plasma exchange improves the speed of response to immunosuppres- sion High-dose steroids and cyclophosphamide May need dialysis. Renal function may not improve and renal transplant is only an option later if anti-GBM ant ibody levels become low Recurrence is uncommon once disease is controlled. It usually respo nds to further immunosuppression. Residual defects in PFTs frequent. \200 Prognosis Rapidly progressive pulmonary hemorrhage and renal failure. Usually fatal if not treated. This page intentionally left blank CHAPTER 51 Vasculitis and the lung 660 Churg \200\223Strauss syndrome De \201 nition and epidemiology Asthma, blood eosinophilia, and an eosinophilic granulomatous in \202 ammation of the respiratory tract, with necroti zing vasculitis affecting small and medium sized vessels. \200 Rare, 2.4 per million population, but 64 per million of an asthmatic population (who may ha ve been misdiagnosed with asthma) Middle-aged adults 2 male:1 female Unknown cause. Montelu kast was postulated as a possible cause, but this is now thought unlikely. Development of C hurg \200\223Strauss syndrome in people on montelukast probably related to their decreased steroid dose \200\230unmasking \200\231 Churg \200\223Strauss syndrome, or as part of an i ncreasing treatment regime in those with uncontrolled asthma, later diagnosed as Churg Stra uss syndrome. \200 \200 Clinical features A diagnosis of Churg \200\223Strauss syndrome can be made if 4 of the fol lowing 6 criteria are present: \200 Asthma \200\224may have had for years, often maturity onset, dif \201 cult to control, ass ociated with rhinitis and nasal polyps \200 Blood eosinophilia >10% \200 Vasculitic neu ropathy, such as mononeuritis multiplex (occurs in 75%) \200 Pulmonary in \201 ltrates \200 Sinus disease \200 Extravascular eosinophils on biopsy \201 ndings. (American Col lege of Rheumatology criteria, 1990) \200 Also may have: \200 Myositis and cardiac failure, cardiomyopathy, coronary artery in \202 am- mation, pericard ial effusion Eosinophilic in \201 ltration of mesenteric vessels causing GI disturbance Al veolar hemorrhage Rarely, proteinuria caused by renal disease with focal segmental glo- mer ulonephritis. Renal failure is rare Skin nodules and purpura Myalgia and arthralgia Fever a nd weight loss. \200 \200 \200 \200 Typical pattern of disease has three phases: beginning with asthma, then developing blood a nd tissue eosinophilia, then going on to systemic vascu- litis. The asthma precedes the vas culitis, often by years (mean 8 years). Investigations \200 CXR Fleeting peripheral pulmonary in \201 ltrates and bilateral multifocal consolidation H RCT Ground-glass in \202 ammation, pulmonary nodules, bronchial wall thickening, or alveol ar hemorrhage Bronchoscopy BAL: marked eosinophilia Pathology Extravascular tissue eosinoph ilia, necrotizing angiitis, granulomata Serum markers Peripheral blood eosinophilia. p-ANCA and anti-MPO positive in two-thirds. ANCA levels may not correlate with disease activity, but blood eosinophilia is a good guide. \200 CHURG \200\223STRAUSS SYNDROME 661 Diagnosis Predominantly a clinical diagnosis. Pathological con \201 rmation of eosinophili c tissue in \201 ltration or vasculitis desirable. Biopsy easiest site affected, such as s kin, kidney, or open or thoracoscopic lung biopsy. Differential diagnosis Allergic bronchop ulmonary aspergillosis, sar- coidosis, drug and parasitic causes of eosinophilic pneumonias , hypersensi- tivity pneumonitis, hypereosinophilic syndrome. Management Depends on severit y of disease at presentation. \200 If isolated pulmonary disease, oral prednisolone 1 mg/kg (max 60 mg/ day) for 1 month or un til no evidence of disease, then slowly decrease over 1 year, with increases if symptoms re cur If unwell, or with alveolar hemorrhage, pulsed methylprednisolone IV for 3 days, follow ed by high-dose oral steroids, with or without cyclo- phosphamide (see p 678 and 680) In ca rdiac or GI disease, relapse, or life-threatening situations, such as requiring organ suppo rt, cyclophosphamide should be added (see p 680) Plasma exchange is of no bene \201 t Trea tment is aimed at reversing organ damage and reducing relapse rate To maintain remission, p rednisolone and one other immunosuppres- sant drug are usually required. Cyclophosphamide i s often changed to azathioprine after 4 \200\2236 months Prophylactic co-trimoxazole should be given (960 mg 3 \227/week) and consider bone protection for steroids Follow-up: regular ly, with checks on FBC and eosinophil count, CXR. Prognosis Good prognosis if isolated pulm onary disease. Good response to steroids. May continue to have asthma despite control of va sculitis, which can be severe and dif \201 cult to control. Poor prognosis associated with cardiac disease and severe gastrointestinal disease, causing bleeding, perforation, or nec rosis. Untreated, 5-year survival rate is 25%. Also associated with worse prognosis: protei nuria >1 g/24 h, renal insuf \201 ciency, CNS involvement. Cardiac disease is the main cau se of death. \200 Further information Noth I et al. Churg \200\223Strauss syndrome. Lancet 2003; 361: 587 \200\22394 www.vasculitis.org 662 CHAPTER 51 Vasculitis and the lung Rare pulmonary vasculitides Polyarteritis nodosa \200 \200 \200 \200 Similar to microscopic polyangiitis, but affects medium-sized vessels May exist as an \200 \230overlap \200\231 disorder with Wegener \200\231s or Churg \200\223Strauss Lung involvem ent is rare Sometimes associated with previous hepatitis B or rarely hepatitis C infection. Takayasu \200\231s arteritis \200 \200 Predominantly young women, often Asian Vasculitis affecting the aorta and its major branche s. Large and medium-sized pulmonary vessels affected, but involvement is usually silent. Pu lmonary artery stenosis and occlusion common, occasionally with mild pulmonary hypertension Presents with fevers and weight loss. Absent or weak upper limb peripheral pulses, particu larly on left (as left axillary artery comes off aortic arch) and arterial bruits Diagnosis made by angiography Treatment Steroids may reduce symptoms, but do not affect mortality. A ngioplasty and surgical procedures may reduce the complications. Spontaneous remissions may occur. \200 Giant cell arteritis \200 Commonest form of systemic vasculitis affecting large- and medium- sized vessels 24 cases p er 100 000. Predominantly elderly females Presents with non-speci \201 c symptoms of fever and weight loss, also headache, scalp tenderness, and jaw pain. Amaurosis fugax and visual loss due to optic neuritis Pulmonary complications occur in 9 \200\22325% of cases. They a re relatively minor, with cough, sore throat, and hoarseness. Pulmonary function tests and CXR normal Diagnosis High ESR, temporal artery biopsy showing pan-arteritis and giant cell formation Treatment Good response to oral steroids. Continue for 1 \200\2232 years. \200 Part 00 Part 3 Supportive care