C MORGAN 444 tolerance and imaging after WLL. Symptoms such as dysp- noea and even cough and chest pain can be relieved by a successful program of WLL. Most importantly the patient feels better. Though invasive, the procedure is inherently safe provided it is undertaken appropriately a nd the airway management is secure. Consider rituximab or other options if the above does not produce remission. Keep all patie nts under review until long established remission is obtained. Other things to consider: \200 The psychological impact of prolonged chronic dysp- noea and repeated hospital episodes. Th e ever present risk of infection of lung and other sites with conventional and unconvention al opportunistic organisms. The principles of rare disease management \200\223 the need fo r concentration of effort and increase in knowledge. Alternative treatments A minority of patients either fail to respond to WLL or they re-accu mulate alveolar material so quickly that the WLL has to be repeated at excessively short in tervals (e.g. less than 1 month). Then alternative options should be considered. The option with by far the most experience so far is the use of exogenous GMCSF. It may seem odd tryi ng to treat an auto-immune disorder with the target of the auto-immunity but John Seymour i n Melbourne treated several PAP patients with daily sub-cutaneous GMCSF injections successf ully before the existence of the anti- GMCSF antibody was appreciated. Around half of that series of patients obtained remission and the non-responders suffered no obvious harm. Many more patients have subse- quently demonstrated a similar response rate and absence of seri ous side effects. The drug is very expensive however, and there have been great dif \201 c ulties with reliable supply because of pharmaceutical issues. An alternative approach, to s ave money and to deliver the drug to its actual site of action is to use the aerosol inhala tion route and there have been very promising results from this approach (11 out of 12 pati ents in Mayo Clinic study). There have been anecdotal reports of use of plasmapher- sis to remove the causative antibody or to switch off its production using the selective agent rit uximab but much less experience than for WLL and GMCSF. The ideal management of PAP: \200 Con \201 rm the diagnosis of PAP. \200 Look for and rule out differential diagnoses or condi- tions which cause secondary PAP or aggravate primary PAP. Confirm the presence of th e anti-GMCSF antibody (requires assay at specialist center). Treat \200\223 WLL \201 rst then move on to aerosol inhaled GMCSF in patients who do not remit after 6 episodes of WLL . Further reading Beccaria M, Luisetti M, Rodi G, et al. Long-term durable bene \201 t after whole lung lavage in pulmonary alveolar proteinosis. Eur Respir J 2004; 23: 526 \200\22353 1. Characteristic pulmonary pathology. Proc. Natl. Acad Sci 1994; 91:5592 \200\2235596. Kitamura T, Tanaka N, Watanabe J, et al. Idiopathic pulmonary alveo- lar proteinosis as an autoimmune disease with neutralizing anti- body against granulocyte-macrophage colony stimu lating factor. J Exp Med 1999; 190:875 \200\223880. Ramirez RJ, Schult RB, Dutton RE. Pulmonary alveolar proteinosis: a new technique and ratio nale for treatment. Arch Intern Med 1963; 112:419 \200\223431. Rosen SH, Castleman B, Liebow AA. Pulmonary Alveolar Proteinosis. N Engl J Med 1958; 258:1123 \200\2231142. Seymour JF, Dunn AR, Vincent JM, et al. Ef \201 cacy of granulocyte- macrophage colony-sti mulating factor in acquired alveolar proteinosis. N Engl J Med 1996; 335: 1924 \200\2231925 . Seymour JF, Presneill JJ. Pulmonary alveolar proteinosis: progress in the \201 rst 44 yea rs. Am J Respir Crit Care Med 2002; 166: 215 \200\223235. Stanley E, Lieschke GJ, Grail D, et al. Granulocyte/macrophage colony-stimulating factor-de \201 cient mice show no major p ertur- bation of hematopoiesis but develop a characteristic paulmonary pathology. Proc Natl Acad Sci USA 1994; 91: 5592 \200\2235596. Trapnell BC, Whitsett JA, Nakata K. Pulmonary alveolar proteinosis. N Eng J Med 2003; 349: 2527 \200\2232539. Wylam ME, Ten R, Prakash UBS, et al. Aerosol granulocyte- macrophage colony-stimulating fac tor for pulmonary alveolar proteinosis. Eur Respir J 2006; 27: 585 \200\223593. This page intentionally left blank T MAHER & D GEDDES 446 18.2 Churg \200\223Strauss syndrome Churg \200\223Strauss syndrome is a multi-system disorder that typically occurs in severe a sthmatics. It is characterized pathologically by granulomata and necrotising eosi- nophilic vasculitis. Estimated annual incidence is 2.4 \200\2236.8 per million. Mean age of onset i s 48 years. Males and females are equally affected. Etiology is poorly understood; key fact ors in the devel- opment of Churg \200\223Strauss syndrome appear to be atopy and asthma, a nti-MPO (myeloperoxidase) autoantibod- ies and the toxic effects on tissues of activated eo si- nophils. Leukotriene antagonists have been linked to over 160 cases of Churg \200\223St rauss syndrome. It is postulated that this is due to a tapering of corticosteroid dosage in patients with hitherto unsuspected Churg \200\223Strauss syn- drome rather than direct dru g toxicity. Cardiac: this occurs in 40% of patients and is associated with signi \201 cant mortality. May present as: eosinophilic endomyocarditis, coronary vasculitis, valvular dysfunc- tion, or pericarditis. Cardiac failure is the commonest presentation. Gastrointestinal: abdominal pain, diarrhea, and or bleeding occurs in up to 60% of patients. Histological changes can occur throughout the GI tract but are most common in the small intestine and colon. Bowel p erfora- tion is the most serious pcomplication. Renal glomerulonephritis is common, renal f ailure how- ever, is rare Cutaneous may include: erythema, pustules, vesicles, ulcers, skin nodules or palpable purpura. Examination Examination \201 ndings are dictated by pattern of organ involvement. The foc us of examination in the patient with suspected Churg \200\223Strauss syndrome should be: ( 1) con- \201 rming the diagnosis; (2) identifying sites for biopsy and (3) characterizing the extent of organ involvement. Disease classi \201 cation Individuals with Churg \200\223Strauss syndrome may manifest a spectrum of abnormalities that frequently make the diag- nosis a challenging one to con \201 rm. A number of classi \201 ca- tion schemes have been developed in an attempt to sys tematize the diagnosis of this condition. The American College of Rheumatology classi \201 cation criteria (Table 18. 2. 1) are the most applicable in the clinical setting. Investigation As with examination, investigations should be aimed at con \201 rming diagno sis and assessing the pattern and extent of organ involvement. Laboratory \200 Table 18.2.1 American college of rheumatology classi \201 cation scheme for Churg \200\223 Strauss syndrome FBC characteristically shows a marked eosinophilia (>1500 cells/ L). This may \202 uctua te and is often masked by corticosteroids. ANCA (anti-neutrophil cytoplasmic antibodies) is posi- tive in a peri-nuclear pattern in half of patients with Churg \200\223Strauss syndro me. This should be con \201 rmed by demonstration of anti-MPO antibodies. In \202 ammator y markers (ESR, CRP) will be raised in active disease and provide a useful measure of respo nse to therapy. Diagnosis of Churg \200\223Strauss syndrome is likely when at least four criteria are prese nt (sensitivity 85%, speci \201 city 99.7%) (1) Asthma (2) Blood eosinophilia >10% (3) Neuropathy (mononeuropathy or polyneuropathy) (4) Pulmonary in \201 ltrates (5) Paranasal sinus abnormality Radiology The most common \201 nding on chest imaging is transient, multi-focal, non-segm ental consolidation (Fig. 18.2.1). Other features include; ground glass change, interlobula r septal thickening, nodules (which may become miliary), adenopathy and pleural effusions. (6) Extravascular eosinophil in \201 ltration on biopsy History Classically, Churg \200\223Strauss syndrome occurs in phases, beginning with asthma , then eosinophilia and ultimately multi-system necrotising vasculitis. Onset of systemic d is- ease is typically heralded by fever, weight loss, fatigue and malaise. Other symptoms r e \202 ect the speci \201 c pattern of organ involvement. \200 Pulmonary: almost all patients have pre-existing asthma and this tends to worsen over the c ourse of the disease. Occasionally there is paradoxical improvement in asthma with the onse t of vasculitis. Pulmonary vasculitis, pleuri- tis and effusions may also lead to symptoms. Upper airway: three-quarters of patients have allergic rhinitis. Other disease manifestati ons include; recurrent sinusitis, nasal polyps, purulent or bloody nasal discharge and, mor e rarely, septal perforation. Neurological: mononeuritis multiplex occurs in up to 65% of c ases. The lower limbs are more commonly affected than the upper limbs. Rarer manifestations occur include; ischaemic optic neuropathy, cerebral hemorrhage, psychosis and seizures. Fig. 18.2.1 HRCT of Churg \200\223Strauss syndrome showing patchy peripheral consolidation, ground glass attenuation and interlobular septal thickening. CHAPTER 18.2 Churg \200\223Strauss syndrome 447 Histology The classical histological lesion of Churg \200\223Strauss is a necr- otising sma ll vessel vasculitis with associated granulomata and eosinophilic tissue invasion. It is un usual to \201 nd all features present within a single biopsy. Treatment failure/disease relapse For patients with good prognosis disease who fail to resp ond to corticosteroids or who relapse following initial response, second-line therapy shoul d be with intravenous cyclophosphamide (as for bad prognosis disease). Patients relapsing a fter initial successful treatment for bad prognosis disease should undergo re-induction the rapy with corticosteroids and cyclophosphamide. Intravenous immunoglobulins (2mg/kg over tw o days every month) and/or monthly plasma exchange are accepted therapy for cases refractor y to corticosteroids and cyclo- phosphamide. Because of the rarity of Churg \200\223Strauss syndrome few treatments have been subject to rigorous evaluation. The biological therapies , rituximab, interferon A and omalizumab have been reported, in small numbers of patients, to be effective in treating Churg \200\223Strauss syndrome and should be considered in case s refractory to conventional therapy. Other Will depend on organ involvement but should include; urine dipstick, 24-hour urine co llection for protein estima- tion, ECG and echocardiogram. Differential diagnosis The range of possible differential diagnoses is wide and is dictated by the predominant phase of the disease. \200 Allergic phase: poorly controlled asthma, allergic bron- chopulmonary aspergillosis (ABPA), or acute extrinsic allergic alveolitis. Eosinophilic phase: eosinophilic pneumonia (acute or chronic), drug induced eosinophilia, helminth infection, Loef \202 er \200\231s syndrom e, or ABPA. Vasculitic phase: Wegener \200\231s granulomatosis, microscopic polyangiitis or polyarteritis nodosa. Prognosis Generally prognosis in Churg \200\223Strauss syndrome is good. overall remission rates are 81 \200\22392 %. Approximately a quar- ter of patients in remission relapse. Half do so within the first year and the remainder after a mean period of 5 years. Five year su rvival exceeds 90%. Ten-year survival in a French cohort of patients was 79%. AUTHOR S TIP The vasculitides are generally considered to be separate diseases. However, in clinical practice there is consider- able overlap between these conditions, often to the e xtent that it is not possible to make a precise diagnosis. Complications Patients with Churg \200\223Strauss syndrome may deteriorate due to: (1) infe ction; (2) drug toxicity; (3) disease relapse; or (4) new unrelated pathology. Infection ca n be particu- larly dif \201 cult to discriminate from disease relapse. Relapses often pre sent with a recrudescence of symptoms present at original diagnosis. However, in a proporti on of patients, previously uninvolved organs may become affected result- ing in new symptom s and signs. Management Disease strati \201 cation Five factors predict poor prognosis disease. These a re: proteinuria >1g/day, serum creatinine >140 moles/l, car- diomyopathy, GI involvement and central nervous system involvement. The presence of one or more of these fea- tures sho uld prompt treatment for bad prognosis disease. Good prognosis disease Initial management revolves around high dose corticoster- oids. Cons ider oral prednisolone 1mg/kg/day. In severe cases initial treatment with pulsed intravenou s methyl- prednisolone (15mg/kg every 24 hours for 3 days) enables more rapid establishment of disease control Corticosteroids can be gradually tapered once an improve- ment in clini cal and in \202 ammatory marker parameters is seen. No hard and fast rules are available t o guide long term ster- oid dosage. A proportion of patients with Churg \200\223Strauss syn drome remain on lifelong, low dose corticosteroids. Follow up and disease monitoring Churg \200\223Strauss syndrome can relapse after many year s remission. Furthermore, asthma often remains a signi \201 cant problem even when systemi c vasculitis is controlled. Pati- ents should therefore remain under long term follow-up. N o serological marker exists to discriminate between qui- escent and active Churg \200\223St rauss syndrome. Assessment at follow up should consist of clinical history and examination with judicious use of ancillary investigations such as in \202 am- matory markers, FBC (fo r eosinophilia) and serum ANCA. Further reading Bosch X, Guilabert A, Espinosa G et al. Treatment of antineutrophil cytopla smic antibody associated vasculitis: a systematic review. JAMA 2007; 298: 655 \200\223669. Bad prognosis disease Cyclophosphamide in combination with corticosteroids should be used i n disease with bad prognostic features. Cyclophosphamide is best tolerated when given intra ve- nously. The typical dosing regimen for IV cyclophosphamide is 600mg/m2 every 2 weeks fo r 4 weeks then monthly for 6 to 12 months. Guillevin L, Lhote F, Gayraud M et al. Prognostic factors in Polyarteritis nodosa and Churg \200\223Strauss syndrome: a prospective study in 342 patients. Medicine (Baltimore) 1996; 75: 17 \200\22328. Keogh KA, Specks U. Churg \200\223Strauss syndrome: clinical presenta- tion, ANCA, and leuk otriene antagonists. Am J Med 2003;115: 284 \200\223290. Maintenance therapy Once stopped, cyclophosphamide should be replaced with a less toxic imm unosuppressant. There is little evidence to guide choice. amcmmAlternatives include; azathi oprine, methotrexate, ciclosporin or mycophenolate mofetil. Once long-term remission is est ablished, immunosuppres- sant therapy and corticosteroids should be cautiously weaned over a prolonged period. Masi AT, Hunder GG, Lie JT, et al. American College of Rheumatology 1990 criteria for class i \201 cation of Churg \200\223Strauss syndrome, allergic granulomatosis and angiitis. Art hritis Rheum 1990; 33: 1094 \200\2231100. Noth I, Strek ME, Leff AR. Churg \200\223Strauss syndrome. Lancet 2003; 361: 587 \200\223594. N NISBET & R WILSON 448 18.3 Ciliary dyskinesia Epidemiology PCD inheritance is predominantly autosomal recessive but other inheritance pat terns are possible and extensive loci of mutations are suspected. There is equal prevalence in men and women and it affects between one in 15,000 to 60,000 individuals. Mucociliary clearance is a \201 rst-line defense mechanism which protects epithelial surf aces against inhaled parti- culate matter, including infectious agents. These are trapped i n the mucus layer which is cleared by ciliary beating. Primary ciliary dyskinesia (PCD), al so known as Kartagener \200\231s syndrome (triad of situs inversus, bronchiectasis and sinu si- tis) and immotile cilia syndrome, is a rare disorder of impaired ciliary activity. Cili a are found on the cell surface in the upper respiratory tract and bronchial tree, fallopia n tubes, ductus epididymis and brain ventricles. In the lung they move mucus continually to ward the pharynx. Abnormal cilia do not beat in the normal fashion resulting in reduced muc ociliary clearance and suscepti bility to infection which causes structural lung damage (br onchiectasis). Cilia are made up of microtubules with outer and inner dynein arms containin g ATPase which provides energy for movement at about 14 beats per second (Fig. 18.3.1). Man y gene defects have been identi \201 ed causing cilia abnormalities, the most common being the absence of the outer dynein arms (Fig. 18.3.2). Other defects include absence of the i nner dynein arms, absence of radial spokes, absence of cen- tral microtubules, abnormal len gth of cilia, supernumerary microtubules, abnormal basal bodies, total absence of cilia, an d anatomically normal but functionally abnormal cilia. Clinical approach There is considerable variation in the clinical presentation but the most common features are persistent cough (which in the absence of mucociliary clearance is rel ied on to expel mucus) and recurrent upper and lower respiratory infections. History: key points \200 Neonates may present with respiratory distress and/or pneumonia. Chronic cough and daily sp utum production. Recurrent lower respiratory tract infections are common. Patients may repo rt intermittent haemoptysis. Wheeze occurs in 20% of cases and individuals may have been pr eviously diagnosed as \200\230asthmatic \200\231. Chronic rhinosinusitis and nasal polypos is are frequently reported. Hearing problems with a history of otitis media and grommets in childhood Fatigue and headaches may be caused by chronic sinusi- tis and bronchiectasis; h owever, hydrocephalus has also been associated with PCD. Male infertility may occur due to immotile spermatozoa and women may have subfertility including ectopic pregnancy. Other con genital abnormalities occasionally associated with PCD include transposition of the great v essels, cardiac abnormalities, pyloric stenosis and epispadias. \200 \200 \200 Outer arm } Dynein Inner arm Nexin link Normal cilium Radial spoke Central microtubules Examination: key points \200 Cell membrane Situs inversus occurs in about 50% but only 20 \200\22325% of persons with situs inversus h ave chronic bronchitis and sinusitis. Coarse inspiratory and expiratory crackles may be pre sent on auscultation. Air \202 ow obstruction with wheeze. Conductive hearing loss from ch ronic otitis media. Voice may be nasal in tone due to absence of frontal sinuses. Fig. 18.3.1 Diagram of cilia ultrastructure. \200 \200 AUTHOR \200\231S TIP PCD is an important differential diagnosis of neonatal respiratory dis tress, bronchiectasis when the history begins in childhood, atypical asthma in childhood, u nusu- ally severe upper airways disease, situs inversus, and male infertility. Fig. 18.3.2 (a) Cilia in cross section with normal ultrastructure showing the nine microtub ular doublets that form a circle surrounding two central microtubules. (b) A cross section of a cilia with an outer dynein arm defect. Investigations A diagnosis of PCD is usually made by the identi \201 cation of immotile, d ysmotile or missing cilia. Ciliary dysfunction may also be acquired by pathologies associated with increased airway in \202 ammation such as viral and bacterial infection, allergy and cigarette smoking. Mucoc iliary clearance is also impaired by abnormal airway surface \202 uid production (e.g. cy stic \201 brosis) and abnormal mucus (e.g. watery mucus following viral infection, viscou s mucous with bacterial infection). Saccharin test A 0.5mm particle of saccharin is placed on the inferior tur- binate of the n ose and the time taken for it to be tasted in the mouth is measured. The patient is sat qui etly with head bent forward and instructed not to sniff or blow their nose. A normal result is less than 30 minutes. This technique is CHAPTER 18.3 Ciliary dyskinesia 449 physicians, otolaryngologists, audiologists, physiotherapists, counseling services and fert ility clinics. less reliable than other tests and should only be used in patients older than 10 years. Nasal and exhaled nitric oxide Nitric oxide (NO) is produced by both the upper and lower re spiratory tract. In PCD nasal and exhaled NO are low. Nasal NO <100 ppb indicates need for cilia biopsy. Nasal polyps (obstruction) also causes low nasal NO. Respiratory Daily physiotherapy is essential to prevent exacerbations and progression of di sease. Techniques include postural or autogenic drainage, active cycle of breathing techniq ue, \202 utter devices and exercise programs. Compliance can be very challenging in pedia tric and adolescent patients. Early and effective antimicrobial treatment of exacerbations is essential to minimize progressive lung damage. Antibiotic courses need to be longer and of higher dose than in people without bronchiectasis (usually 10 \200\22314 days minimum). Antibiotics may be oral, intravenous or nebulised and regular sputum surveillance will guid e empiric treatment. Antibiotic prophylaxis may be considered in more severe cases. Variabl e air \202 ow obstruction should be treated with bron- chodilators and inhaled steroids. R outine pneumococcal vaccination and annual in \202 uenza vaccinations should be administer ed. Education on smoking cessation should be provided. Nasal brush or scrape biopsy Biopsies from the inferior turbinate of the nose are exam- ine d by light microscopy and equipment to determine cili- ary beat frequency and pattern. Elec tron microscopy is used to assess ciliary morphology and orientation. It is important not t o confuse primary and secondary abnor- malities and tests should be repeated after treatmen t of infections if there is any uncertainty. Spermatozoa assessment Spermatozoa may be examined for motility and ultrastruc- ture howeve r some patients have immotile cilia but nor- mally motile spermatozoa. Chest radiography Chest radiograph may be normal or may show peribron- chial thickening, hy perin \202 ation, atelectasis and bronchiecta- sis. Dextrocardia is present in up to 50% o f cases. ENT A multidisciplinary approach should be used to manage upper airways disease with surgic al intervention in selected patients for middle ear disease, sinusitis and nasal polyposis. Hearing should be monitored. HRCT Bronchiectasis predominantly affects the middle and lower lobes. Fertility Infertility is not inevitable however patients with PCD will need access to ferti lity services. AUTHOR \200\231S TIP Mucus clearance by physical exercise, physiotherapy and \202 utter d evices reduces the rate of infective episodes. Early and effective treatment of exacerbatio ns is essential to minimize progressive lung damage. Prognosis The prognosis for PCD is generally good. However a sub- set of patients exhibit a more rapid decline with consider- able morbidity and mortality, and the cause is usually m ore serious infections causing bronchiectasis, and then chronic infection and more frequent exacerbations. Further reading Afzelius B, Stenram U. Prevalence and genetics of immotile-cilia Fig. 18.3.3 HRCT demonstrating bilateral lower lobe bronchiectasis with an area of collapse on the right and dextrocardia. syndrome and left handedness. Int J Dev Biol 2006; 50: 2132. Bush A, Cole P, Hariri M, et al. Primary ciliary dyskinesia: diagnosis and standards of care. Eur Resp J 1998; 12: 982 \200\223988. Corbelli R, Bringof-Isler B, Amacher A, et al. Nasal nitric oxide measurements to screen ch ildren for primary ciliary dyskinesia. Chest 2004; 126: 1054 \200\2231059. Pulmonary function tests Spirometry may show mild to moderate airway obstruc- tion with var iable responsiveness to bronchodilators. Gas trapping occurs, and gas transfer values corre cted for alveolar volume are usually normal. Greenstone M, Stanley P, MacWilliam L, et al. Mucociliary function and ciliary ultrastructu re in patients presenting with rhinitis to Brompton Hospital Nose Clinic. Eur J Respir Dis Suppl 1983; 128: 457 \200\223459. Microbiology Routine culture of sputum should be completed. Haemophilus in \202 uenzae is common and Pseudomonas aeru- ginosa when bronchiectasis is more severe. Jain K, Padley S, Goldstraw E, et al. Primary ciliary dyskinesia in the pediatric populatio n: range and severity of radiological \201 ndings in a cohort of patients receiving terti ary care. Clin Rad 2007; 62: 986 \200\223993. Kennedy M, Noone P, Leigh M, et al. High Resolution CT of patients with primary ciliary dys kinesia. Am J Roentgenol 2007; 188: 1232 \200\2231238. Management Early diagnosis is important because early treatment may delay the development o f bronchiectasis as well as avoid unnecessary otorhinolaryngological procedures. Patients s hould be managed by multidisciplinary teams in units with a special interest in PCD with pe diatric and adult chest Noone P, Leigh M, Sannuti A, et al. Primary ciliary dyskinesia: diagnostic and phenotypic f eatures. Am J Respir Crit Care Med 2004; 169: 459 \200\223467. Wilson R. Secondary ciliary dysfunction. Clin Sci (Lond) 1988; 75: 113 \200\223120. S KRAVINSKAS & S JOHNSON 450 18.4 Pulmonary Langerhans \200\231 cell histiocytosis Pulmonary Langerhans \200\231 cell histiocytosis (PLCH) is a rare interstitial lung disease (ILD), characterized by the pres- ence of granulomas containing large numbers of Langerhan s \200\231 cells (LC) that invade and destroy distal bron- chioles. The clinical spectrum o f Langerhans \200\231 cell histiocytosis (LCH) is large, ranging from an acute disseminated form, which has a very poor prognosis and occurs in children, to a more benign form of the disease where lesions are local- ised in single tissues. LCH can be classi \201 ed accord ing to the level of the in \201 ltration to organs. It may affect a single organ, i.e. the lung, bone, lymph nodes, or multiple organs. Abdominal discomfort due to in \201 ltration of liver and spleen. Skin rashes and adenopat hy. Investigation and diagnosis Radiography Abnormalities seen depend on disease stage as the l esions are thought to evolve from nodules to cavitary nodules into thick walled cysts, thin walled cysts and \201 nally \201 brosis. A normal chest radiograph seen in <10% patien ts. Typical chest radiograph \201 ndings: \200 Disease is found in upper and middle lung \201 elds, bilat- eral, diffuse, with sparing o f the costophrenic angles. Lung volumes appear normal or increased, unlike the reduced volu mes seen in other ILDs (with exception of lymphangioleiomyomatosis (LAM)). Recent onset \200\223 poorly demarcated micronodular lesions (<5mm). Medium term \200\223 reticulonodula r shadows with underlying cystic lesions. Long standing \200\223 cystic cavities (few nodu les). Appearance is indistinguishable from advanced emphysema and LAM. Epidemiology PLCH affects 2 \200\2235 per 1,000,000 individuals per year and accounts for f ewer than 5% of ILDs diagnosed by surgical lung biopsy. Numerous studies have shown that ov er 90% of patients have a history of heavy smoking, and adding to this, the bronchiolar dis tribution of the pathologic lesion supports the possibility that an inhaled antigen is invo lved in the pathogenesis of the disease. Although no precise epidemiological data are avail able, it has a peak incidence in young white adults between 20 \200\22340 years old. The re lative frequency of disease in males in comparison to females is unclear, as evidence is ma inly from case series rather than inclusive trials. Early studies suggested a male predomin ance. However, more recently an equal incidence or slight predominance in women has been fo und. This may be due to the increased prevalence of female smokers over recent years. HRCT This allows the nature and distribution of parenchymal abnormalities to be excellently determined, and is capable of showing disease in patients whose chest radiographs are norm al. HRCT frequently shows that reticular abnormali- ties on chest radiograph are actually s hadows produced by multiple cysts (Fig.18.4.1). Clinical presentation The presentation of PLCH varies: \200 66% patients present with persistent respiratory symp- toms, commonly dyspnoea and a non-pr oductive cough. 25% of patients are asymptomatic and the disease is revealed on a routine c hest radiograph. 10% patients present with spontaneous pneumothorax. Constitutional symptom s (33%), haemoptysis (<5%) and rarely chest pain may occur. Physical examination is commonl y normal. The affect of PLCH on pulmonary function depends on the stage of disease and the abnormalities present. Restrictive, obstructive and mixed patterns have been observed. Appr oximately 50% patients show an obstructive pattern, particularly patients with cystic lesio ns from long standing disease. As most ILDs show a restrictive pattern, the pres- ence of o bstructive abnormalities helps in the diagnosis of PLCH. However, obstructive changes may a lso be a result of co-existing COPD. The most commonly described abnormality in pulmonary f unction is a reduction in carbon monoxide transfer factor (70 \200\223100% patients). Howev er, it is dif \201 cult to determine the effect of the disease from that of cigarette smok ing. PLCH is isolated to the lungs in more than 85% of patients. Extra-pulmonary manifestat ions (<15%) include: \200 Fig. 18.4.1 HRCT showing multiple cysts in a patient with advanced LCH. Typically abnormalities are seen interspersed in normal parenchyma, and lesions are equally distributed between central and peripheral portions of the lung with partial sparing of th e bases. NB sparing of lung bases and an irregular shape of cysts help distinguish PLCH fro m LAM. In cases where ground-glass attenuation and/or adenopa- thy are seen, biopsy may be needed to establish diagnosis. Bone pain (20% of patients) due to lesions often in the skull, ribs and pelvis. Polyuria an d polydipsia from pituitary involvement pro- ducing diabetes insipidus. Biopsy Biopsy has largely been replaced by HRCT due to the high sensitivity of imaging. Bro choalveolar lavage, transbronchial biopsy, or surgical lung biopsy may be performed to CHAPTER 18.4 Pulmonary Langerhans \200\231 cell histiocytosis 451 provide morphological evidence for diagnosis. Samples show an increased number of LC, which can be detected under light microscope, positive for CD1 antigen or S-100 staining. If the proportion of CD1a-stained cells is greater than 5%, PLCH is very likely. However, this is not particu- larly helpful as an increased CD1a level is also found in heavy smokers and o ther ILDs. Under electron micros- copy, characteristic intracytoplasmic Birbeck granules ma y be seen. VATS biopsy is mainly used to exclude alternative diagnostic possibilities (Fig. 18.4.2). patients will deteriorate with progressive respiratory insuf- \201 ciency and cor pulmona le. 30 \200\22340% will regress to a lesser extent to be left with persisting thin walled c ysts. 50% patients will undergo partial or complete resolution of radiographic abnormalitie s. Long-term follow-up of all patients is necessary, as even after years of remission, new nodules may form, causing lung function to again deteriorate. Patients \200\231 outcome is likely to improve with the cessation of smoking, therefore this should strongly be encourag ed. Corticosteroids are thought to help accelerate resolution of the disease, particularly in symptomatic patients with systemic symptoms, but precise bene \201 ts remain unclear. C hemotherapeutic agents such as vinblastine and cyclo- phosphamide are used to treat diffuse LCH in children. However limited data is available on their efficacy in PLCH. Lung transpl ant has been successful in patients with advanced disease causing severe respiratory impair ment, or severe pulmonary arterial hypertension. Interestingly, PLCH has later recurred in the transplanted lung in several cases. Although this complication reduces the transplanted lung \200\231s function, the effect on overall survival has not been established. AUTHOR \200\231S TIPS \200 Lack of exposure to smoking and age >60 make diag- nosis unlikely. Typical cases show impai red diffusing capacity and upper-lobe predominance. Smoking cessation is vital to treatment 50% patients undergo resolution. Death from disease is rare. Fig. 18.4.2 Lung biopsy with Langerhans cells labeled with labeled for S-100 protein. (See Plate 16.) Differential diagnosis The ability to establish a diagnosis of PLCH depends on the clinical and radiological \201 ndings. The diagnosis is simple in young smokers presenting with n odular and cystic lesions. If a patient has systemic symptoms and prominent cavitary nodule s the following diseases must be considered: myco- bacterial infection, sarcoidosis, silico sis, Wegener \200\231s disease, cavitary metastatic lesions, alveolar cell carcinoma, septi c emboli, or excavated pneumocystis. LAM must be distinguished from PLCH in women with pure ly cystic lesions. \200 Further reading Caminati A, Harari S. Smoking-related interstitial pneumonias and pulmonary Langerhans cell histiocytosis. Proc Am Thorac Soc 2006; 3: 299 \200\223306. Kim CK, Park BP. Pulmonary Langerhans \200\231 cell histiocytosis pre- sented with recurren t pneumothorax. Interact CardioVasc Thorac Surg 2006; 5: 512 \200\223513. Tazi A, Soler P, Hance AJ. Adult pulmonary Langerhans \200\231 cell histiocy- tosis. Thorax 2000; 55: 405 \200\223416. Treatment and prognosis There are no reliable guidelines regarding treatment and prognosis due to the large variation in outcome seen across patients. Generally, PLCH patients \200 \231 life expectancy is shorter than that of the general population. Poor prognostic factor s include: a very young or very old age at onset of disease, ongoing systemic symptoms, rec ur- rent pnemothoraces and extrapulmonary features (exclud- ing bone involvement). It is un common for the disease to progress to advanced pulmonary fibrosis and death. Approximately 10 \200\22320% Vassallo R, Ryu JH, Colby TV, et al. Medical progress: pulmonary Langerhans \200\231-cell h istiocytosis. N Engl J Med 2003; 342(26): 1969 \200\2231978. Vassallo R, Ryu JH, Schroeder DR, et al. Clinical outcomes of Pulmonary Langerhans \200\231 -cell histiocytosis in adults. N Engl J Med 2002; 346(7): 484 \200\223490. Vassallo R, Jensen EA, Colby TV, et al. The Overlap Between Respiratory Bronchiolitis and D esquamative Interstitial Pneumonia in Pulmonary Langerhans Cell Histiocytosis. Chest 2003; 124(4): 1199 \200\2231205. S JOHNSON 452 18.5 Lymphangioleiomyomatosis Lymphangioleiomyomatosis (LAM) is a rare cystic lung dis- ease which almost exclusively aff ects women. The disease is associated with angiomyolipomas, benign tumors gen- erally occur ring in the kidneys and abnormalities of the axial lymphatics. Epidemiology LAM affects 1 \200\2232 per million of the general population (sporadic-LAM) b ut is common in tuberous sclerosis com- plex (TSC-LAM) where lung cysts are present in up t o 40% of adult women. Presentation and clinical features Most patients present between 20 and 50 years of age wit h dyspnoea or pneumothorax. Cough and wheezing are common in LAM and can lead to misdiagnos is of more common conditions. Diagnosis may follow CT scanning performed for other purposes . Less often hemorrhage from renal angiomyolipoma or symptomatic abdominal or pelvic lympha tic masses are the \201 rst symptom. LAM is exacerbated by, and may present during, pregn ancy. Missed presentations of LAM \200 \200 \200 \200 \200\230Emphysema \200\231 in younger women. \200\230Asthma \200\231 unresponsive to ther apy. Pneumothorax during pregnancy. Respiratory symptoms in TSC. Cysts develop in the lungs causing dyspnoea in most patients. Pneumothorax occurs in two th irds of patients and is frequently recurrent. Occlusion of the axial lymphat- ics results i n lymphadenopathy, cystic abdominal and pelvic masses (lymphangioleiomyomas), chylous pleur al effusions and ascites. Abdominal discomfort, bloating, or pressure symptoms occur in up to 20%. Half of patients have one or more angiomyolipomas, benign tumors of smooth muscle, fat, and blood vessels. Angio myolipomas occur mainly in the kidneys and can bleed when lar ge. A small number of patients have menin- giomas. Fig. 18.5.1 HRCT of patients with LAM. Upper panel is asymptomatic disease with minimal cys ts (arrowed) and normal parenchyma. Lower panel shows extensive disease. Investigation and diagnosis Plain radiographs may be normal in early disease or show inters titial markings with preserved lung volumes. HRCT scanning shows lung cysts with thin walls evenly distributed within normal lung parenchyma (Fig. 18.5.1). The cysts become more nume rous as the disease progresses. 80% of patients have abnormalities on abdominal imaging: 50 % with renal angiomyolipomas and a signi \201 cant number with lymphadenopathy, lymphangio leiomyomas, or chylous ascites. Abdominal CT is recommended to identify these complications , to explain abdominal symptoms and to screen for angiomyolipoma which has a characteristic appearance due to its fat content (Fig. 18.5.2). Lung function tests may be normal in earl y disease but air \202 ow obstruction with impaired gas transfer is commonly seen. Pleural complications and their treatment may lead to restrictive changes. Pathological samples sh ow abnor- mal smooth muscle type cells (LAM cells) proliferating in the lung to form nodule s which protrude into small airways and line the walls of cysts (Fig. 18.5.3). Biopsy of ex tra-thoracic lymphatics shows tissue in \201 ltrated LAM cells. Fig. 18.5.2 Angiomyolipoma in the left kidney. Characteristic mixed attenuation tumor (arro w) of low density suggesting presence of fat. Although morphology is characteristic, immunostaining for the melanoma-related protein GP10 0 with the antibody HMB45 is a helpful marker especially in early disease. LAM cells are al so smooth muscle actin and often estrogen and progesterone-receptor positive. CHAPTER 18.5 Lymphangioleiomyomatosis 453