Etiology and pathology 548 Chest disease: clinical features 550 Chest disease: management 5 52 General management 554 Extra-thoracic disease 1 556 Extra-thoracic disease 2 558 548 CHAPTER 45 Sarcoidosis Etiology and pathology De \201 nition \200 A multisystem in \202 ammatory disorder of unknown cause, likely resulting from the interp lay of environmental and genetic factors Characterized by non-caseating granulomata and CD4 Th1-biased T-cell response in affected organs Commonly involves the respiratory system, bu t can affect nearly all organs 50 \200\22360% of people have spontaneous remissions; others may develop chronic progressive disease Etiology Incidence varies with population studies, from 5 to 100/100 000, according to geog raphic distribution. UK incidence is about 5 \200\22310/100 000. Commoner in African-Americ ans, West Indians, and the Irish. Commonly presents between ages of 20 and 40. Unusual in c hildren and the elderly. Typically more aggressive disease in Black populations than in Cau casians \200\224especially with skin disease, peripheral lymphadenopathy, bone marrow, and liver involvement; higher relapse rates and worse long- term prognosis Genetics Familial and ethnic clustering of cases suggest a genetic predispo- sition. Siblin gs of an affected person have a 5x increased risk of developing sarcoidosis. Best evidence of HLA association comes from recent large multicentre ACCESS study, showing HLA-DRB1*0301 is associated with susceptibility to disease in Blacks and Whites. Also a genome-wide scan for susceptibility genes in familial sarcoidosis has been performed, pointing to a locus on chromosome 5 in African-Americans and chromosome 6 in German Caucasians. Pathology Sarcoid osis is caused by an immunological response: \200 Unknown antigenic stimulus triggers CD4 (helper) T-cell activation and expansion. This resp onse is exaggerated and Th1-biased, with resultant interferon gamma and IL-2 production fro m these T-cells Activated T cells proliferate and release mediators, attracting additional in \202 ammatory cells with concomitant macrophage activation and aggre- gation This leads to immune granuloma formation, which is enhanced by inter- feron gamma Granulomata themsel ves cause increased local \201 broblast stimulation and hence \201 brosis Metabolic act ivity of macrophages causes raised ACE (angiotensin- converting enzyme) levels in serum, lu ng tissue, and bronchoalveolar \202 uid. Increase in T-cell activity causes B-lymphocyte stimulation, which can cause raised serum immunoglobulins and immune complexes In most pati ents, response resolves over 2 \200\2235 years Delayed-type hypersensitivity reactions are depressed in sarcoidosis. This is thought to be due to the migration of lymphocytes to the active com- partment (lungs), with resultant pe ripheral blood lymphopenia. Seen as a decreased response to tuberculin, mumps virus, and Ca ndida albicans antigens. This is not thought to be clinically signi \201 cant. etiology AND PATHOLOGY 549 Sarcoid-like reactions are reported in association with malignancy and also in HIV patients starting on antiretroviral therapy (very rare). Non-caseating pulmonary granulomas are fou nd, but there are no other symptoms or signs of sarcoidosis. Differential diagnosis of granuloma on lung biopsy \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 Sarcoidosis Tuberculosis Extrinsic allergic alveolitis Wegner \200\231s granulomatosis Prim ary biliary cirrhosis Granulomatous orchitis Langerhans cell histiocytosis Leprosy Tertiary syphilis Brucellosis Berylliosis Silicosis Hypogammaglobulinaemia Fungal infections \200 \224coccidioidomycosis Schistosomiasis Cat scratch fever Lymphoma Giant cell arteritis Poly arteritis nodosa Takyasu \200\231s arteritis Crohn \200\231s disease De Quervain \200\231s thyroiditis Further information Iannuzzi MC. Advances in genetics of sarcoidosis. Proc Am Thorac Soc 20 07; 4: 457 \200\22360. Schurmann M, Lympany PA et al. Familial sarcoidosis is linked to the major histocompatabili ty complex region. Am J Respir Crit Care Med 2000; 162: 861 \200\2234. Schurmann M, Bein G et al. HLA-DQB1 and HLA-DPB1 genotypes in familial sarcoidosis. Respir Med 1998; 92: 649 \200\22352. 550 CHAPTER 45 Sarcoidosis Chest disease: clinical features More than 90% of patients with sarcoidosis have thoracic i nvolvement, with an abnormal CXR. Pulmonary sarcoidosis can be an incidental CXR \201 ndi ng in approximately 30% of patients. There is spontaneous remission in two-thirds and 10 \200\22330% have a chronic course. Clinical features There are probably at least 2 distinct clinical courses: \200 L fgren \200\231s syndrome Mild acute disease, which is usually non-progres- sive. Presents with fever, bilateral hilar lymphadenopathy, erythema nodosum, and arthralgia. Occurs particularly in Caucasians. Has a good prognosis and resolves comple tely and spontaneously in 80% within 1 \200\2232 years. A minority may develop lung disease Persistent progressive in \201 ltrative lung disease Hilar/mediastinal lymphadenopathy May be asymptomatic or cause cough or chest pain. Often b ilateral and symmetrical, but can be unilateral and asymmetrical. Can be associated with sy stemic symptoms of malaise and arthralgia, which are helped by non-steroidal anti-in \202 ammatory drugs. Benign course. Important to exclude other causes of lymphadenopathy, such as TB and lymphoma. May need HRCT and lymph node aspirate or biopsy. Does not require systemic steroid treatment. Stage I: 85% resolve spontaneously over 2 years, 15% develop lung in \201 l- trates. The a verage time for bilateral hilar lymphadenopathy resolution is 8 months Interstitial lung in volvement May be asymptomatic or cause morbidity and mortality, with dyspnoea, cough, chest ache or frank pain, malaise, fatigue, and impaired quality of life. Rarely have crackles o r clubbing on examina- tion. Pulmonary in \201 ltrates on CXR. Can return to normal over t ime, or progress to \201 brosis and respiratory failure. Lung function tests may be norma l, or may show a restrictive defect with reduced transfer factor. Differential diagnosis Ot her interstitial lung disease, malignancy, infection. Radiological classi \201 cation of thoracic sarcoidosis Stage 0 Stage I Stage II Stage III Stage IV Normal Hilar lymphadenopathy Hilar lymphadenopathy and parenchymal in \201 ltrate Parenchy mal in \201 ltrate Fibrosis CHEST DISEASE: CLINICAL FEATURES 551 Seeing a patient with possible sarcoidosis in clinic \200 Make diagnosis \200\224clinical ly, HRCT histology \200 Assess extent/severity/presence of extrapulmonary involvement \200\224 CXR, PFT, ECG, eyes, rash, renal function, serum calcium, liver function, immunogl obulins, and ACE (latter two can be raised in active sarcoidosis) Stable or progressive? \200\224CXR, PFT (VC 9 KCO), oximetry, ACE, urea (if renal involvement) Treatment? Differential diagnosis of bilateral hilar lymphadenopathy on CXR \200 \200 \200 \200 \200 \200 \200 Sarcoidosis Tuberculosis Lymphoma Coccidioidomycosis and histoplasmosis Leukemia Berylliosi s Hypogammaglobulinaemia and recurrent infections. Further information Judson MA, Baughman RP et al. Two year prognosis of sarcoidosis: the AC CESS experience. Sarcoidosis Vasc Diffuse Lung Dis 2003; 20: 204 \200\22311. 552 CHAPTER 45 Sarcoidosis Chest disease: management Diagnosis is based on a characteristic clinical picture, plus: \200 \200 \200 Histological evidence of non-caseating granuloma in any tissue Characteristic picture on im aging (thoracic HRCT scan or gallium scan) Lymphocytosis on bronchoalveolar lavage (BAL) Other diseases capable of producing similar clinical and histological picture, particularly tuberculosis and lymphoma, should be excluded. Investigations \200 HRCT Micronodules in a subpleural and bronchovascular distribution. Fissural nodularity and bronchial distortion. Irregular linear opaci- ties, ground-glass shadowing related to bron chovascular bundles, and nodular or ill-de \201 ned shadows. Air-trapping due to small air way granu- lomata common. Endobronchial disease in 55%. Possible honeycomb lung. Hilar and mediastinal lymphadenopathy. CT-guided FNA of sub- carinal or mediastinal nodes may be poss ible and yield a tissue diagnosis Bronchoscopy (transbronchial biopsy, TBNA, bronchial biop sy, or bronchoalveolar lavage) may not be necessary if there is no diagnostic doubt clinica lly and radiologically. Positive yield of bronchial biopsy is 41 \200\22357%. Higher if vis ible abnormal mucosa. Positive yield of trans- bronchial biopsy is 40 \200\22390% (still hi gh yield even if lungs appear normal on HRCT). This is the initial procedure of choice in a patient with suspected pulmonary sarcoidosis. Transbronchial needle aspiration (TBNA) of t he mediastinal lymph nodes will yield a diagnosis in 63 \200\22390% of cases. Transbronchia l biopsy and TBNA have a higher yield together than either alone. Experience is limited in endoscopic ultrasound FNA (EUS-FNA) in sarcoidosis. BAL in sarcoidosis shows a CD4:CD8 rati o of >3.5. If this test is not available, a lymphocytosis of >2 \227 105cells/mL supports the diagnosis, but is not diagnostic. (Lymphocytosis is also seen in UIP, COP, hypersensiti vity pneumonitis, and smokers) Mediastinoscopy for central or paratracheal nodes or open lu ng biopsy: 90% positive yield. May be necessary to exclude lymphoma. Surgical biopsy is not usually necessary, but if other procedures have not yielded a de \201 nitive diagnosis, i t may be required. Lymph node lung (usually via VATS) can be biopsied. Biopsy other affe cted areas such as skin, liver, etc. if indicated, as these may be easier to biopsy in orde r to make a diagnosis Mantoux/Heaf test may show minimal reaction/grade 0 in sarcoid (perip heral cutaneous anergy to tuberculin due to migration of T cells to active sites of disease ). A positive Mantoux or Heaf test therefore make sarcoidosis less likely as a diagnosis, a lthough does not necessarily make tuberculosis more likely as the diagnosis. Heaf testing n ot widely used now. Kveim test No longer performed clinically, due to risks of transmissibl e diseases. It involved injecting homogenized splenic tissue from a patient with sarcoidosi s to see if a granulomatous reaction occurred. CHEST DISEASE: MANAGEMENT 553 Monitoring disease There is no single measurement to assess all the aspects of patients wit h sarcoidosis. Clinical examination and serial meas- urements are key. \200 PFT Pulmonary sarcoidosis gives a restrictive defect with decreased TLC and VC. TLCO provid es the most sensitive measurement of change, although a properly performed VC is probably a dequate for clinical purposes. Likely to improve with steroids. Air \202 ow obstruction ma y also occur CXR may improve with time or treatment ACE (angiotensin-converting enzyme) lev els increased in up to 80% of patients with acute sarcoidosis, although can be normal in ac tive disease. It may be a surrogate marker of the total granuloma burden. Levels become nor mal as disease resolves. Can be useful to monitor the clinical course, if activity is uncer tain, but levels should not be used in isolation to determine treatment. Levels suppressed by steroids and when steroids are stopped levels usually increase, unrelated to sarcoid- os is activity. This is not a speci \201 c test. False positives include TB Calcium may rise with active sarcoidosis or in the summer months. This may cause renal impairment, so urea o r creatinine should also be checked BAL not performed routinely to assess progress of sarco idosis, but changes in proportions of cells seen in lavage would indicate improve- ment PET scan may be positive in areas of disease activity. Not reliable for studying brain or hear t. Limited studies of serial data Gallium scan rarely used now, as non-speci \201 c and ex pensive. Areas of active in \202 ammation are positive, with a classic \200\230panda patt ern \200\231. Positive areas soon become negative with steroid use. Bowel and liver positiv e anyway, so disease cannot be charted in these areas. \200 554 CHAPTER 45 Sarcoidosis General management Most patients with pulmonary sarcoidosis do not require treatment. Asymp tomatic CXR in \201 ltrates are usually monitored. Indications for immunosuppressive treatment \200 Increasing symptoms, deteriorating PFTs, and worsening CXR in \201 ltrates Cardiac sarcoid osis Neurosarcoidosis Sight-threatening ocular sarcoidosis Hypercalcaemia Lupus pernio Sple nic, hepatic, or renal sarcoidosis. \200 \200 \200 \200 \200 Starting drug treatment \200 When required, treatment is usually with steroids initially. Good evi- dence for short to m edium term improvement in symptoms, respira- tory function, and radiology, but long-term be ne \201 ts less clear Give high doses, such as 40 mg prednisolone/day, to control active d isease. Rarely need more than 40 mg/day. Usually give this high dose for 4 weeks and then r educe if there has been a response Maintenance dose of around 5 \200\22320 mg, to control s ymptoms. Leave on this dose for a few months and then slowly reduce steroid dose further. M aintain on low dose of prednisolone (5 \200\2237.5 mg/day or alternate days) for prolonged period of up to 12 months to consolidate resolution, before considering complete withdrawal . Some patients, especially those with progressive pulmonary sarcoidosis, may require longe r treatment (years) of low-dose prednisolone to prevent relapse Inhaled steroids are of lim ited ef \201 cacy in sarcoidosis, but may be useful if there is cough or bronchial hyperre activity Relapses often occur when treatment is stopped and may require the reintroduction of steroids, or the increase of steroid dose. Duration and dose of steroids is dictated by site and response to treatment Avoid futile steroid treatment for end-stage disease, such a s honey- comb lung If steroid treatment fails, or sarcoidosis is life-threatening, other im mu- nosuppressive regimes may be indicated. Pulsed high-dose intravenous methylprednisolone is an option, which can be particularly useful for neurosarcoidosis In cases where prolong ed immunosuppression is required, or if steroid side-effects cannot be tolerated, other imm unosuppressive drugs should be considered. Possibilities include azathioprine and methotrex ate. There are limited data for their use in sarcoidosis Patients who have troublesome symp toms related to sarcoidosis, such as arthralgia, skin disease, fever, sweats, ocular sympto ms, systemic symptoms such as fatigue, may require symptomatic steroid treatment. GENERAL MANAGEMENT 555 Lower initial doses such as 20 mg/day are likely to be suf \201 cient to gain symptomatic control and doses can then be reduced Prescribe gastric and bone protection with steroids w hen necessary Other drugs used in sarcoidosis (See p 601 for more information regarding immunosuppressive drugs.) If there is progressive pulmonary sarcoidosis, refractory to steroids, con- sider: \200 Methotrexate Given once/week 15 \200\22325 mg PO for 6-month trial. Use instead of or in ad dition to low-dose prednisolone. Avoid if hepatic or renal failure. Side-effects: GI upset, stomatitis, pneumonitis, myelosup- pression. Teratogenic. Low oncogenic potential. Monitor FBC and MCV, AST, ALT every 2 weeks for 3 months, then monthly. Do not use for >2 years. U seful for chronic sarcoidosis and cutaneous disease Azathioprine Used in neurosarcoidosis a nd stage II/III pulmonary sar- coidosis with partial/no steroid response. 100 \200\223150 m g/day. Use instead of or in addition to low-dose prednisolone. Side-effects: myelosup- pres sion, GI upset, stomatitis, idiosyncratic reaction \200\223fever, rash. Low oncogenic poten tial. No gonadal toxicity. Check FBC every 2 weeks for 3 months, then monthly. TPMT (thiopu rine methyltransferase) testing should be performed prior to commencement (see p 678) Cyclo phosphamide IV pulsed, for neurosarcoidosis unresponsive to steroids. Toxicity pro \201 le limits use. (See p 681) Anti-malarials Chloroquine and hydroxychloroquine 200 mg od/bd. Fo r skin and hypercalcaemia. Steroid sparing. Can be given with steroids and other immunosupp ressant in severe sarcoidosis. Side-effects: rarely, ocular toxicity Others New unproven ef \201 cacy: ciclosporin, thalidomide, TNFA inhibitors (etanercept, in \202 iximab) Prognosis There are no prognostic markers in sarcoidosis, apart from: \200 Good prognosis L fgren \200\231s syndrome has complete resolution in 80% of people Poorer prognosis with chronic disease Lupus pernio, nasal mucosa involve- ment, chronic uveitis, chronic hyperca lcaemia, nephrocalcinosis, neural involvement, age greater than 40 and Black race Prognosis according to CXR appearance: \200 Stage II: 50% cases recover spontaneously in 2 years, 30 \200\22340% require systemic stero ids, 10 \200\22315% require long-term steroids Stage III: Worse prognosis. Only 30% show si gni \201 cant improvement with steroids Transplant Consider if patient has end-stage lung disease, rapidly pro- gressive disease de spite treatment, or if they are oxygen dependent. Sarcoidosis is a rare indication for lung transplant. Granulomata recur in transplanted lung, but do not cause higher rates of graft failure. 556 CHAPTER 45 Sarcoidosis Extra-thoracic disease 1 Varies according to ethnic origin and sex of patient. Systemic sym ptoms are common, such as fever, sweats, loss of appetite, weight loss, fatigue, malaise, c hest pain, dyspnoea, and cough. Polyarthralgia often affects the knees, ankles, wrists, and elbows, and can be improved by NSAIDs. Hypercalcaemia Granulomata convert vitamin D3 to ac tive 1,25-dihy- droxycholecalciferol. This causes enhanced calcium absorption from intes- t ine. Sunlight also increases levels of vitamin D and calcium. High calcium may cause system ic effects and is often associated with renal damage and hypercalciuria. Commoner in Caucas ians and in men. Treatment If mildly raised, limit dietary calcium intake, avoid sun expo- sure and drink pl enty of \202 uids. Otherwise, steroids, often low dose once calcium level controlled (sho uld be within 2 weeks \200\224if not investigate for other cause for hypercalcaemia). Decre ase dose when calcium level satis- factory. Some patients may only need steroids during the summer months. Hydroxychloroquine can also be used. Skin 25% of patients have skin involve ment. More common in women. Erythema nodosum Raised papules, nodules, or plaques, usually o n shins. Also tender, indurated, or bruised appearance. Firm and often have shiny appearanc e. Nodular change involving different tattoo colors recognized and is characteristic of sar coidosis. Sarcoid tissue may arise in old scars, or cause scar hypertrophy. Lupus pernio is a bluish tinge that occurs on nose, cheeks, and ears. It is associated with chronic diseas e. Diagnosis Usually easily biopsied Treatment Initially with topical preparations. Lupus pernio should be treated with systemic steroids. Hydroxychloroquine or methotrexate may be necessary. Role of long-term tetracycl ines for cutaneous sarcoidosis under investigation Eye Common, occurring in 25% plus of cas es, especially women and African-Caribbeans Uveitis (acute or chronic), episcleritis, scler itis, glaucoma, conjunctivitis, and retinal involvement can occur. May be asymptomatic, or cause painful red eye, with photophobia, lacrimation, and blurred vision. Pupil irregular o r constricted. Untreated, can cause visual impairment. Lacrimal involvement in sarcoidosis gives keratoconjunctivitis sicca \200\224dry eye with diminished tear secretion. Painful re d eyes. Treat with arti \201 cial tears. Diagnosis Assessment by an ophthalmologist with slit lamp examina- tion if any ocular sympt oms. Some recommend that all newly diagnosed patients with sarcoidosis have slit lamp exami nation. Mild asymptomatic eye involvement is common. May need conjunctival biopsy, if no ev idence of sarcoid elsewhere. Treatment Local steroids are commonly used if there is no other indica- tion for systemic s teroids. However, if it does not respond, systemic ster- oids should be used. EXTRA-THORACIC DISEASE 1 557 Heart Cardiac sarcoidosis occurs in 5% of patients with pulmonary disease. Post mortem stud ies show cardiac sarcoidosis is present in 25%, so is often undiagnosed. Patients may prese nt with chest pain or, more com- monly, are found to have conduction defects on the ECG. Th ese may be benign and asymptomatic, like \201 rst-degree heart block, but more signi \201 cant arrhythmias can occur, the \201 rst indication of which may be sudden death. My ocardial granulomata can occur in any part of the heart. Commonly they occur in the interve ntricular septum, where they can affect nodal and conducting tissue. The left ventricular w all can be affected, with \201 brosis causing reduced compliance and contractile dif \201 culties, leading to cardiac failure. Aneurysms can form, and pericarditis can occur. V alvular dysfunc- tion due to in \201 ltration of the papillary muscles is rare. The clinic al course can be uncertain. Diagnosis Echocardiogram may show signs of cardiomyopathy \200\224usually restrictive. MRI, technetium scan, or gallium scan show non-segmental \201 xed defects. Biopsy is diagnost ic, but can be dif \201 cult as sarcoidosis is patchy. Not recommended in general. ECG and 24-h tape may be helpful in investigation. Treatment Must be treated with systemic steroids 20 \200\22340 mg prednisolone/ day, which improve symptoms and ECG and Echo features. These should be slowly reduced, but intractable arrhythmias may need continued high dosage. May need other immunosuppressants. Investigate with 24-h tape if uncertain. Amiodarone, a pacemaker, implantable de \201 brillator, or h eart transplant may be necessary. In clinic Perform a screening ECG on all patients with sarcoidosis perhaps every 6 months. 558 CHAPTER 45 Sarcoidosis Extra-thoracic disease 2 Kidney A degree of renal involvement is found in 35% of patients w ith sarcoidosis. Rarely can present with renal failure, obstructive uropathy, nephrolithias is, or urinary tract disorder. Nephrocalcinosis is a common cause of chronic renal failure. Often associated hypercalcaemia or other manifestation of sarcoidosis. Diagnosis Renal biopsy with granulomata found in interstitium, but this is rarely needed in this context. Search for pulmonary sarcoidosis. Treatment Steroids hydroxychloroquine for hypercalcaemia. CNS Involved in 4 \200\22318% of patients. Can affect any part of the peripheral or central nervous system. Can present a s a peripheral nerve or cranial nerve lesion. Most common is lower motor neuron facial nerv e palsy, with optic nerve involvement being next commonest. Mononeuritis multiplex recogniz ed. May be less speci \201 c, with psychiatric features. Hypothalamic granulomata may caus e diabetes insipidus, appetite disturbance, or hyper- somnolence. Diagnosis Dif \201 cult, but may be made easier if there is another sign of sys- temic sar coidosis, for example bilateral hilar lymphadenopathy. Lumbar puncture may show a raised CS F ACE and an increased lymphocyte count. Con \201 rm with biopsy if possible \200\224cereb ral or meningeal tissue if no pul- monary involvement. Treatment Must be treated with steroids, but often quite resistant to treatment. May need t o try further immunosuppressants. Musculoskeletal Arthralgia is common in sarcoidosis, but arthritis is unusual. Arthralgia commonly affects the ankles and feet, but also hands, wris ts, and elbows. A subacute proximal myopathy can occur, as well as bone cysts, especially o f terminal phalanges. The latter show little response to systemic steroids. Diagnosis Granuloma seen on muscle biopsy. Treatment NSAIDs; steroids may be necessary. GI 60% of liver biopsies on patients with sarc oidosis show granuloma. Frequently asymptomatic. Hepatomegaly unusual, but can get portal \201 brosis and cirrhosis. LFTs suggestive if 3 \227 normal, especially ALP and GGT. Diagn osis Biopsy. Treatment Steroids \200\224may reduce size of liver and improve LFTs. EXTRA-THORACIC DISEASE 2 559 Hematological Splenomegaly can occur and may be massive, causing abdominal discomfort. A ma ssive spleen may require splenectomy to avoid rupture. Associated anemia, neutropenia, and thrombocytopenia. Lymphopenia often seen. ENT Nasal or laryngeal granuloma. Sinus invasion. Parotid and other sali- vary gland enlargement, dry mouth. Rarely Breast disease, ovarian or testicular masses. Further information Judson MA, Iannuzzi MC (Eds). Sarcoidosis: evolving concepts and contro versies. Sem Respir Crit Care Med 2007; 28. American Thoracic Society/European Respiratory Society/World Association of Sarcoidosis and other Granulomatous Disorders statement on sarcoidosis. Eur Respir J 1999; 14: 735 \200 \2237. Guidelines for the diagnosis and assessment of diffuse parenchymal lung disease. Thorax 199 9; 54(suppl. 1): S1. Judson MA, Baughman RP et al. Two year prognosis of sarcoidosis: the ACCESS experience. Sar coidosis Vasc Diffuse Lung Dis 2003; 20: 204 \200\22311. World Association of Sarcoidosis and other Granulomatous Disorders website, www.pinali.unip d. it/sarcoid This page intentionally left blank 561 Chapter 46 Sickle cell disease: pulmonary complications Overview 562 Acute chest syndrome 564 Sickle cell chronic lung disease 566 562 CHAPTER 46 Sickle cell disease Overview Background Sickle cell disease is an autosomal recessive condition resulting in a substitu- tion of a valine for glycine in the beta-globin subunit of hemoglobin (Hb), formi ng HbS. HbS is less soluble under reduced oxygen tensions and leads to deformation of red b lood cells (sickling) when deoxygenated (for example, in atelectatic lung), resulting in ch ronic haemolysis and vascular occlusion with tissue infarction in individuals homozygous fo r the beta- globin gene mutation (sickle cell anemia/disease). Hemoglobin electro- phoresis or high-performance liquid chromatography (HPLC) in sickle cell disease demonstrates HbS 80 \200\22399% and no normal hemoglobin HbA; anemia Hb 6 \200\2239 g/dl is usual. Heterozyg ote carriers of the beta-globin gene mutation are referred to as having \200\230sickle cel l trait \200\231 and are largely asymptomatic, although sickle crises may occur during extr eme hypoxia (e.g. during anesthesia); HPLC analysis demonstrates HbS 35 \200\22340% and Hb A (normal hemoglobin) 50%. Sickle hemoglobin solubility testing does not distinguish betwe en trait and homozygous disease. Pulmonary complications \200 Obstructive airways disease and airway hyper-reactivity is often noted on pulmonary functio n testing; pathogenesis unclear Nocturnal oxyhaemoglobin desaturation is common, pathogenes is unclear \200\224tonsillar hypertrophy is common, and OSA may be a contri- buting factor Pneumonia is more common, particularly from Chlamydia pneumoniae, S. pneumoniae, H. in \202 uenzae, Mycoplasma, Legionella and respiratory viruses; may precipitate acute chest sy ndrome. Invasive pneumococcal disease is signi \201 cantly more common. Patients should ta ke lifelong pro- phylactic penicillin, as functionally asplenic Pulmonary thromboembolism a ppears to be more common; may pre- cipitate acute chest syndrome Acute chest syndrome Sickl e cell chronic lung disease \200 This page intentionally left blank 564 CHAPTER 46 Sickle cell disease Acute chest syndrome De \201 nition and clinical features De \201 ned as new pulmonary in \201 l- trates on CXR, associated with symptoms such as fever, cough, chest pain and brea thlessness. A form of acute lung injury; may progress to ARDS. Leading cause of death in si ckle cell disease; occurs in up to half of all patients during their lifetime. Risk factors include young age, high steady state leukocyte counts and hemoglobin levels, and past hist ory of acute chest syndrome. May follow surgery and anesthesia. Causes may not be apparent, and include one or more of infection, pul- monary fat embolism (preceded by bony pain), in situ thrombosis or pul- monary embolism, atelectasis following hypoventilation (from acute painful crisis of chest wall or excessive opiates), and possibly pulmonary oedema due to e xcessive hydration. Each leads to hypoxia with increased sickling and vascular occlusion, a nd initially mild disease can escalate rapidly to ARDS and death. All patients with a painf ul vaso-occlusive crisis should be monitored closely for the development of the acute chest syndrome; routine use of incentive spirometry may help prevent its development in these pa tients. Investigations \200 \200 Blood tests Raised white cell count, anemia; check HbS % Hypoxia is common and may be under estimated using pulse oximetry; A \200\223a gradient predicts clinical severity; consider I TU transfer if worsens Culture blood and sputum CXR shows multifocal pulmonary in \201 ltr ates, sometimes with pleural effusion BAL may be considered in patients not responding to t reatment. \200 ACUTE CHEST SYNDROME 565 3 Management of sickle cell acute chest syndrome Supportive care on ITU may be required. Liaise with hematology team. Treatment comprises: \200 \200 \200 \200 Oxygen to correct hypoxia; monitor ABGs Empirical broad-spectrum antibiotics (including a m acrolide) Rehydration (IV \202 uids may be needed; care to avoid overhydration) Bronchodi lators are often used; air \202 ow obstruction is common, may contribute to high airway pr essures during mechanical ventilation Ensure adequate analgesia for bony pain (consider NSA IDs; IM or SC opiates often required) Incentive spirometry and chest physiotherapy to preve nt atelectasis. Pain may limit their use, and CPAP may be better tolerated Simple and excha nge blood transfusion both reduce the HbS concentration and improve oxygenation in acute ch est syndrome. Indications for transfusion include persistent or worsening hypoxia, severe d isease, multilobar involvement, neurological complications, multi-organ failure, or history of cardiac disease. Simple transfusion is recommended if severely anemic, although Hb shou ld not be raised above 10.5 g/dl as the increase in blood viscosity exacerbates sickling. E xchange transfusion should be used in patients with a relatively high Hb, aiming for HbS <2 0% and maintaining total Hb <14.5 g/dl Other treatments. Successful use of inhaled nitric o xide for the treatment of a handful of refractory cases has been reported. Corticosteroids may be of bene \201 t in children, but rebound pain crises may occur and routine use of co rticosteroids is not recommended. Hydroxyurea increases fetal Hb and reduces sickling, and signi \201 cantly reduces the incidence of acute chest syndrome; it is recommended for pat ients with recurrent episodes. Prognosis Approximately 13% of patients with acute chest syndrome require mechanical ventil ation; overall mortality 4 \200\2239%.