Clinical features \200 Oral and oesophageal ulceration shortly after contact, with later for- mation of a pseudome mbrane Renal failure (reversible) within a few days, but delayed excretion of paraquat prev ents falls in blood levels Pulmonary oedema early on, evolving into \200\230acute respirat ory distress syndrome \200\231 Death usually occurs within 1 to 2 weeks Pulmonary \201 br osis if the patient survives, with varying degrees of recovery. \200 22 Management \200 Gastric lavage with Fuller \200\231s earth/bentonite/activated charcoal/ sodium resonium to reduce absorption Haemoperfusion (haemodialysis less effective) to reduce blood levels Low est inspired oxygen tension possible (high concentrations prob- ably increase superoxide fo rmation) Supportive measures which may require intubation and ventilation Other treatments (e.g. immunosuppression, NO) are experimental. \200 \200 RADIATION-INDUCED PULMONARY DISEASE 601 Radiation-induced pulmonary disease Manifestations of lung injury following radiotherapy in clude: Radiation pneumonitis \200 Often asymptomatic, although may cause dyspnoea and chronic ventila- tory failure Radiograp hic abnormalities more common than clinical disease. Characteristically straight margins on CT in \201 ltrate Pathological feature is of diffuse alveolar damage, with vascular intim al \201 brosis Typically follows lung radiotherapy Treatment of symptomatic disease is wi th steroids (1mg/kg daily), although minimal evidence to support their use. Amifostine or p ent- oxifylline (used in the treatment of extrapulmonary manifestations of radiation-induce d tissue damage) may be of bene \201 t, although unproven. \200 Radiation-induced organizing pneumonia \200 Often presents with cough (rather than breathlessness, which is more suggestive of radiatio n pneumonitis) Characterized by migratory patchy consolidation which always extends beyond radiation \201 eld on CT Typically follows breast radiotherapy Treatment is with steroids ; often long courses are needed. Macrolides may have a role. \200 Radiation-induced chronic eosinophilic pneumonia \200 Possible association; few cases reported. 602 CHAPTER 48 Toxic agents Inhalational lung injury 1 De \201 nition Agents damaging the lung and airways through dir ect tox- icity. Much of the acute damage is common to many toxic agents including pneumonit is/pulmonary oedema, mucosal damage/sloughing/airway debris. Secondary infection is common due to breached defenses. 22 Management of inhalational lung injury \200 \200 \200 \200 Following acute exposure, supportive therapy is critical Look for respiratory failure, stri dor, or distress; may occur hours later CXR (poor sensitivity until pulmonary oedema develo ps) May need intubating/tracheostomy to bypass oedematous and sloughing upper airway mucosa Humidi \201 ed oxygen: \200 Raise SaO2 into low/mid 90s (higher levels may contribute to oxidative damage) Raise PaO2 a s high as possible if CO poisoning suspected Treat cyanide poisoning if suspected (dicobalt edetate, little evidence) Bronchodilators Ne bulized dilute heparin/acetylcysteine \200\224variable opinions on value Steroids and proph ylactic antibiotics \200\224variable opinions on value Mechanical ventilation (low volume/p ressure, permissive hypercapnia) Fluid replacement, but not excessive as encourages pulmona ry oedema Enteral feeding. \200 \200 \200 \200 \200 Examples of toxic agents, listed alphabetically Aldehydes (acetaldehyde, formaldehyde) \200 \200 \200 Chemical and plastics industry, used for disinfection Highly irritant to mucosal membranes Acute damage \200 Chronic effects \200 Pneumonitis and pulmonary oedema Rhinitis/asthma Ammonia \200 \200 \200 Fertilizer and plastics production, used in many chemical industries Highly irritant to muc osal membranes Acute damage \200 \200 Chronic effects \200 Upper airway obstruction from secretions and mucosal oedema Lung damage and secondary infec tion Airways obstruction and bronchiectasis described Chlorine \200 \200 Extensive use in the chemical industry, bleaching agent Acute damage \200 \200 Chronic effects (e.g. from repeated accidental exposure) \200 Overwhelming toxicity producing rapid hypoxia Pneumonitis and pulmonary oedema Airways obstruction; sometimes reversible INHALATIONAL LUNG INJURY 1 603 Cocaine (when smoked) \200 \200 \200 \200 Pneumothorax/pneumomediastinum Pulmonary hemorrhage Pulmonary oedema Allergic responses (as thma, pulmonary eosinophilia, hypersensitivity pneumonitis) Metals and metal compounds (as fumes or nebulized solutions) \200 \200 Mainly used in the chemical industry Acute damage \200 \200 Chronic effects \200 Some speci \201 c effects such as: \200 \200 \200 Mucosal irritation Pulmonary oedema Pneumoconiosis Sarcoid-like reaction to beryllium Asthma/from cobalt, chromium, nickel, vanadium Fibrosing alveolitis from cobalt and zinc fumes Methyl isocyanate (Bhopal disaster: 3800 dead, 170 000 injured) \200 \200 Chemical industry, carbamate pesticides Acute damage \200 \200 Chronic effects \200 \200 \200 Pneumonitis and pulmonary oedema Secondary infection Airways obstruction Bronchiolitis obliterans Pulmonary \201 brosis Hydrocarbons/mineral oils \200 \200 Used as lubricant and cooling agent Acute damage Pneumonitis \200 Chronic effects Pneumon itis \200 Fibrosis \200 Asthma \200 Nitrogen dioxide \200 \200 \200 \200 Chemical industry (explosives) Agricultural silos Odorless and therefore high doses inhaled without knowing Acute damage (several hours after exposure) \200 Later effects \200 \200 Silo \201 llers lung (pneumonitis/pulmonary oedema) Secondary pulmonary oedema 2 \200\2238 weeks after exposure Steroid responsive, needs 2 mon ths therapy after exposure. 604 CHAPTER 48 Toxic agents Inhalational lung injury 2 More examples of toxic agents Ozone \200 \200 \200 \200 Bleaching agent Product of welding Similar to NO2 Both immediate and late effects of pneumo nitis/pulmonary oedema Phosgene \200 \200 \200 Chemical warfare, chemical industry, chlorination Released from heated methylene chloride ( paint stripper) Acute damage \200 \200 Pneumonitis and pulmonary oedema Produces COHb; breath CO therefore re \202 ects degree of exposure Smoke \200 \200 Most smoke injury is due to heat damage to upper airway Hypoxia, vaporized toxins (e.g. for maldehyde, chlorine), systemic agents (e.g. CO and cyanide) Acute damage \200 Look out fo r: \200 \200 \200 \200 \200 \200 Mucosal oedema and sloughing with airway blockage Peri-oral burns Black sputum Altered voice Respiratory distress Stridor (rapid inspiration to accentuate) Additional CO and/or cyanide poisoning Sulfur dioxide \200 \200 \200 Used as a fumigant, and bleaching agent in the paper industry Very irritant as dissolves to form sulphuric acid Acute damage \200 \200 Chronic effects \200 Sloughing of airway mucosa Pneumonitis and haemorrhagic pulmonary oedema Airways obstruction Welding fumes \200 \200 Many agents released Speci \201 c examples: Cadmium \200\224pneumonitis \200 Zinc \200 \224 \200\230metal fume fever \200\231 \200 Several agents may cause airways obstruction/ COPD \200 Siderosis (welders lung) non- \201 brogenic pneumoconiosis \200 Iron deposits in lung producing small rounded opacities This page intentionally left blank 606 CHAPTER 48 Toxic agents Carbon monoxide poisoning De \201 nition and epidemiology \200 Carbon monoxide is a colorless odorless gas formed when carbon compounds burn in limited ox ygen It accounts for about 75 deaths per year in the UK, approximately 10% of which are acc idental Accidental poisonings are commoner in the winter when faulty heating systems are in use Non-accidental deaths are mainly from car exhaust fumes Methylene chloride (industrial solvent, paint remover) is converted to CO in the liver and may present as CO poisoning Up to one-third die following acute high level exposure and another third may be left with pe rmanent neurological sequelae Chronic low-grade CO exposure may present as non-speci \201 c ill health and may affect thousands of individuals. \200 Pathophysiology and related conditions \200 Carbon monoxide competes avidly with O2 (250 times greater) to bind with the iron in hemogl obin, making it less available for oxygen carriage The hemoglobin molecule is also distorte d by combination with CO that makes it bind more tightly to O2, shifting the O2 dissociatio n curve to the left. The PaO2 at which the hemoglobin is 50% saturated (P50) moves from abo ut 3.5 to 2 kPa This further reduces oxygen delivery to the tissues: a 50% carboxyhae- mogl obin level is far more dangerous than a 50% anemia CO also binds to extravascular molecules such as myoglobin and some of the cytochrome chain proteins interfering with energy produc tion, and in this respect is like cyanide Normal levels of carboxyhaemoglobin can be up to 3%, and up to 15% in heavy smokers Fetal hemoglobin combines even more avidly with CO; thus the fetus is especially vulnerable to CO poisoning of the mother. Methaemoglobin \200 Methaemoglobin is due to oxidation of Fe2+ to Fe3+ thus preventing O2 carriage. This is due either to inherited de \201 ciencies of enzymes (cytochrome b5 reductase) that reduce the Fe3+ back to Fe2+, or toxic agents (e.g. nitrites (in \200\230poppers \200\231), chloroqu ine) that overwhelm this reversal mechanism Methaemoglobin is slightly left shifted, but a 40% methaemoglobinaemia may be asymptomatic apart from the typical gray/blue color of the p atient, often mistaken for cyanosis. CARBON MONOXIDE POISONING 607 Clinical features of CO poisoning Immediate \200 \200 Nausea, headache, malaise, weakness, and unsteadiness Loss of consciousness, seizures, card iac abnormalities (ischaemia, arrhythmias, pulmonary oedema) No cyanosis, healthy looking \200\230cherry red \200\231 color Suspect if several members of household present with thes e features \200 Delayed (approximately 1 to 3 weeks, can be longer) \200 \200 Cognitive defects and personality changes Focal neurology and movement abnormalities Investigations \200 Pulse oximetry will appear normal due to COHb having similar absorp- tion spectra to oxyhae moglobin Arterial PaO2 levels may be normal COHb levels can be measured on a Co-oximeter Br eath CO measured with devices used for smoking cessation work Routine tests to rule out oth er diagnoses. \200 \200 \200 22 Management of CO poisoning \200 CO is only removed from the body through displacement by O2; therefore use high concentrati ons of oxygen, e.g. via CPAP masks (p 732) Raise the PaO2 as high as possible, intubate and 100% O2 if necessary The half-life of COHb breathing air is about 6 h; breathing 100% O2 i t is about 1 h Hyperbaric O2 more rapidly displaces CO and increases dissolved O2. Reduces the frequency of delayed neurological symptoms from 46% to 25% following signi \201 cant e xposure in one randomized con- trolled trial, but needs to be instituted early. Still contr oversial, recent Cochrane report equivocal, and facilities poorly available. \200 Future developments Isocapnic hyperpnoea may further raise the PaO2. Alkalosis must be avoi ded though, to prevent further left shift of the Hb dissociation curve. Can be done volunta rily with 5% CO2 in O2 or during intubation. Can double rate of CO elimination. Further information Blumenthal I. Carbon monoxide poisoning. J R Soc Med 2001; 94: 270 \200 \2232. Cochrane review of hyperbaric oxygen, http://www.cochrane.org/reviews/en/ab002041.html +44 (0)1752209999. Plymouth Diving Disease Research Center, 24hr helpline and register of h yperbaric chambers. Harper A, Croft-Baker J. Carbon monoxide poisoning: undetected by both patients and their d octors. Age and Ageing 2004; 33: 105 \200\2239. Kreck et al., Isocapnic Hyperventilation Increases Carbon Monoxide Elimination and Oxygen D elivery. http://ajrccm.atsjournals.org/cgi/content/full/163/2/458 This page intentionally left blank 609 Chapter 49 Unusual conditions (BOLD) British Orphan Lung Disease (BOLD) project 610 Alveolar microlithiasis 611 Amyloidosis: pat hophysiology and classi \201 cation 612 Amyloidosis: lung involvement 1 614 Amyloidosis: l ung involvement 2 616 Hereditary haemorrhagic telangiectasia 618 Idiopathic pulmonary haemo siderosis 620 Langerhans \200\231 cell histiocytosis 622 Lymphangioleiomyomatosis (LAM): cl inical features 624 LAM: diagnosis and management 626 Primary ciliary dyskinesia (PCD) 628 Pulmonary alveolar proteinosis (PAP): pathophysiology and clinical features 630 PAP: diagnosis and treatment 632 Pulmonary arteriovenous malformations (PAVMs): etiology and diagnosis 634 PAVMs: management and complications 636 Recurrent respiratory papillomatosis 637 610 CHAPTER 49 Unusual conditions (BOLD) British Orphan Lung Disease (BOLD) project The British Orphan Lung Disease (BOLD) register was set up by the British Thoracic Society in 2001 to facilitate research into rare lung di s- eases and improve clinicians \200\231 knowledge of these conditions. It also aimed to he lp establish patient support groups. In continental Europe there have been registers of rare lung diseases for many years. The t erm \200\230orphan \200\231 lung disease was coined because of the feeling that these dise ases have, in the past, tended to be neglected because of their rarity, the limited knowled ge of the conditions, and the limited available data on which to base practice. The reporting system works via a web-based registration form, where consultants are encoura ged to enter details of patients with any of the listed conditions. The data is anonymized, and the patient must sign a form (found on the BTS website at www.brit-thoracic.org.uk in the members only section) consenting for their details to be held on a central database. In terested parties are invited to submit research proposals, for which the collected data wil l be used. The BOLD register collects data on: \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 Alveolar proteinosis Churg \200\223Strauss syndrome Ciliary dyskinesia Cryptogenic organizi ng pneumonia Langerhans \200\231 cell histiocytosis (histiocytosis X) Lymphangioleiomyomato sis Neuro \201 bromatosis with lung disease Primary pulmonary hypertension Primary trachea l tumors Pulmonary arteriovenous malformations (including HHT) Tracheo/bronchial/pulmonary amyloidosis. Rare lung disease patient support groups: \200 \200 \200 \200 \200 \200 Lymphangioleiomyomatosis Action \200\224www.lamaction.org UK Histiocytosis Family Support A ssociation \200\224www.hrtrust.org Pulmonary Hypertension Association UK \200\224www.pha-uk .com Churg \200\223Strauss syndrome \200\224www.vasculitis-uk.org Pulmonary Alveolar Protei nosis \200\224 www.papfoundation.org/ (USA) Primary Ciliary Dyskinesia Family Support Group \200\224 www.pcdsupport.org.uk/ Alpha-1 antitrypsin de \201 ciency \200\224www.alpha1.org .uk/ Amyloid \200\224http://www.amyloidosis.org/whatisit.asp (USA) Hereditary Haemorrhagic Telangiectasia \200\224www.telangiectasia.co.uk/ \200 \200 ALVEOLAR MICROLITHIASIS 611 Alveolar microlithiasis This is a rare interstitial lung disease of unknown etiology, chara cterized by the accumulation of numerous and diffuse calci \201 ed microliths (calcium and phosphate hydroxyapatite bodies) in the alveolar space. There is no identi \201 able abno rmality of calcium metabolism. Microliths are occasionally identi \201 ed in the sputum. A t post mortem the lungs are heavy and rock hard, often needing a saw to cut them. Fewer tha n 200 cases are reported. Clinical features \200 Typically presents in young adults, most commonly in the third and fourth decades of life M ay be an incidental CXR \201 nding in asymptomatic patients Familial tendency \200\224pro bable autosomal recessive inheritance Equal sex distribution in sporadic cases, 2:1 female preponderance in familial cases Usually slowly progressive, with progressive breathlessness , hypoxia, respiratory failure, and death CXR and chest CT show \201 ne micronodular lung calci \201 cation, pre- dominantly basally or around the hila. It may produce complete ra dio- graphic opaci \201 cation. There is no associated lymph node enlargement. Progressive lung in \201 ltration causes restriction of lung movement and impairs gas exchange, leadi ng to progressive respiratory failure. \200 \200 Treatment \200 \200 There is no effective medical treatment Lung transplantation has been successful. 612 CHAPTER 49 Unusual conditions (BOLD) Amyloidosis: pathophysiology and classi \201 cation De \201 nition Amyloidosis is the ext racellular deposition of low molecular weight protein molecules as insoluble \201 brils. More than 20 such proteins have been described in different diseases and circumstances. Pat hophysiology The disease is one of abnormal protein folding, and is classi \201 ed by the origin of the precursor proteins that form the amyloid. For example, AL amyloid forms from the light chains of immunoglobulins. In familial forms, genetic missense mutations produce abnormal folding of the protein. Little is known of the speci \201 c genetic and environme ntal factors that lead to the development of this abnormal folding. Despite their different origins, these protein molecules fold into alternative forms that are very similar to each other: in the classic \200\230B-pleated sheet \200\231 structure, \201 brils form in an ordered fashion, with uniformity of \201 bril structure within the sheet. Substitutions of particular amino acids at speci \201 c positions in the light-chain variable region lea d to destabilization of the light chains, increasing the chance of \201 brillogenesis. In certain models, this abnormal folding can be initiated by the addition of \200\230amyloid enhancing factor \200\231, rather like the initiation of crystal formation in a supersatur ated solution. Amyloid deposits accumulate in the extracellular space, disrupting normal ti ssue architecture and leading to organ dysfunction, both directly, and having space-occupyi ng effects. The \201 brils may be directly cytotoxic (possibly by promoting apoptosis). T he subdivisions of amyloid are largely based on the origin of the amyloid protein and shown in the box opposite. Epidemiology The epidemiology is dif \201 cult to de \201 ne accura tely as the disease is often un- or misdiagnosed. The age-adjusted incidence is estimated t o be 5.1 \200\22312.8 per million person years. Future developments Anti-amyloid drugs are under investigation, including drugs to stabilize the amyloid precursor proteins in their n ormal con \201 guration and enhance \201 bril degradation. AMYLOIDOSIS: PATHOPHYSIOLOGY AND CLASSIFICATION 613 Classi \201 cation of amyloidosis \200 Primary/light chain amyloid (AL), from immunoglobulin light chain fragments ( or ), usu ally monoclonal due to a plasma cell dyscrasia (a subtype of lymphoproliferative disorders) \200 \200 \200 1 in 5000 deaths due to this type of amyloid Median survival is 6 \200\22315 months Frank m yeloma is present in 20%, and a subtle monoclonal gam- mopathy in 70% (MGUS) Systemic form due to circulating monoclonal light chains, wide- spread organ involvement, particularly he art, liver, and kidneys Localized amyloid production by local clonal B cells; hence heterog eneous organ involvement is seen, commonly in the upper respiratory tract and orbit, with u rogenital and gastrointestinal involvement \200\224virtually any organ (except the brain) c an be involved Secondary amyloid (AA) \200 A complication of chronic disease with ongoing/recurring in \202 am- mation, e.g. rheumato id, chronic infections The \201 brils are fragments of acute phase reactant, serum amyloi d A Commonly renal, hepatic, and lower GI involvement, rarely neuro- logical, lung, and car diac involvement Median survival 5 years Only a small number of patients with chronic in \202 ammation will develop AA amyloidosis, and the time period for the development of the d isease is very variable \200 \200 Dialysis-related amyloid (DA), due to \201 brils derived from B2 micro- globulin that acc umulate in dialysis patients Inherited amyloidosis, e.g. due to abnormal pre-albumin (trans - thyretin, TTR), damaging neural and cardiac tissue Organ-speci \201 c amyloid, such as A lzheimer \200\231s disease; plaques of the B protein derived from the larger amyloid precur sor protein (APP). Protein presumed to be generated locally. 614 CHAPTER 49 Unusual conditions (BOLD) Amyloidosis: lung involvement 1 Clinically signi \201 cant respiratory tract disease is al most always AL in type, though the presence of a strong family history or chronic in \202 ammatory disease may suggest other types. Laryngeal amyloidosis Amyloid causes up to 1% of benign laryngeal disease. May present as discrete nodules or diffuse in \201 ltration, and is usually localized, though can be a rare manifestation of systemic (AL) amyloid. Deposit s are seen most commonly in the supraglottic larynx (presenting with hoarse voice or strido r). May present with choking and exertional dyspnoea that can be progressive or recurrent. Tracheobronchial amyloid is rare (67 worldwide cases reported by the mid-1980s). Macroscopi cally is either diffusely in \201 ltrative or \200\230tumor-like \200\231. It is associat ed with tracheobronchopathia osteoplastica (a disorder char- acterized by the deposition of calci \201 ed submucosal airway nodules). It presents after the \201 fth decade with dy spnoea, cough, and rarely haemo- ptysis. Airway narrowing can lead to atelectasis or recurr ent pneumonia; solitary nodules may lead to investigation for presumed lung cancer. Symptom atic disease is usually localized. Parenchymal amyloid is the most frequently diagnosed amyloid respiratory disease. It is usu ally divided radiologically into solitary/multiple pulmonary nodules (usually localized AL amyloid) or a diffuse alveolar pattern (usually a manifestation of systemic AL amyloid). Pa renchymal amyloid lung nodules are usually peripheral and subpleural, may be bilateral, and are more common in the lower lobes, ranging in diameter from 0.4 to 15 cm. They may cavita te or calcify. Clinical signs are non-diagnostic, PFTs may show a restrictive defect with r educed transfer factor. The differential diagnosis usually includes \201 brosis. Cardiac amyloid may coexist, and distinguishing the contribution to the symptoms of the pulmonary a nd cardiac disease can be dif \201 cult. Median survival with clinically overt lung diseas e is about 16 months (similar to that of systemic amyloid). Mediastinal and hilar amyloidosis are rarely associated with localized pulmonary amyloidosi s and their diagnosis should lead to a search for a systemic cause of amyloid. Amyloid lymp hadenopathy can also represent localized AL deposition in association with B-cell lymphoma. Other Rare reports of: \200 Ventilatory failure due to diaphragm or other respiratory muscle involvement Sleep apnoea f rom macroglossia due to amyloid Exudative pleural effusions. \200 Clinical features \200 \200 Dyspnoea and cough None \200\224parenchymal disease may be an incidental \201 nding on ro utine radiography Consider the diagnosis particularly in patients with odd upper airway sym ptoms and parenchymal involvement, or those with unexplained congestive cardiac failure or nephrotic syndrome. AMYLOIDOSIS: LUNG INVOLVEMENT 1 615 Diagnosis Histological con \201 rmation is usually required. Congo red stain producing \200\230apple green \200\231 birefringence in crossed polarized light is the gold standard. Positive histology must lead to immunohistochemistry to deter- mine the \201 bril type. \200 Histology Transbronchial biopsy or occasionally open or VATS biopsy (more likely if investi gation for solitary pulmonary nodule). 123I labeled scintigraphy Radiolabelled serum amyloi d P (SAP) local- izes to amyloid deposits in proportion to the quantity of amyloid present, therefore allowing identi \201 cation of the distribution and burden of disease. It is mo st sensitive for solid organ disease, though in lung disease is useful for determining the extent of disease in other organs. It is, however, expensive and carries an infection risk, as the serum amyloid P component is currently obtained from blood donors. HRCT may show no dules or parenchymal disease. Laryngoscopy and bronchoscopy may be needed to obtain samples for histology, depending on the clinical presentation. PFTs to assess the effect of diseas e on respiratory function. May show reduced transfer factor and a restrictive pattern. Trac heobronchial involvement may lead to abnormal \202 ow \200\223volume loops due to larger airway obstruction. Systemic disease \200 \200 \200 FBC, biochemistry, and urinalysis (?renal involvement) Investigate for underlying blood cel l dyscrasia, e.g. myeloma, Waldenstrom \200\231s macroglobulinaemia (bone marrow examinatio n, and search for urine and serum monoclonal protein by immuno \201 xation \200\224 the cl onal proliferation underlying systemic AL amyloid is usually very subtle, and its identi \201 cation may be dif \201 cult) Echo for associated cardiac involvement (when congestive cardiac failure is present, survival is 4 \200\2236 months) Thyroid/adrenal function are i mpaired in up to 10%. 616 CHAPTER 49 Unusual conditions (BOLD) Amyloidosis: lung involvement 2 Treatment There are limited clinical trials with which to g uide manage- ment of respiratory tract amyloid. Management decisions are therefore often ma de empirically. \200 \200 No treatment may be needed Local measures may be warranted for endobronchial disease, e.g. symp- tomatic laryngeal disease \200\224endoscopic excision, carbon dioxide laser evaporati on (useful for small recurrent lesions), stenting. Steroids have no effect on laryngeal amy loid Tracheobronchial amyloid \200\224management depends on symptoms and treatment may invo lve repeated endoscopic resection, YAG (yttrium \200\223 aluminum \200\223garnet) laser the rapy, and surgical resection. Repeated endoscopic procedures are thought to be safer than r epeated open surgery Chemotherapy may be warranted for diffuse parenchymal amyloid if there is objectively measurable disease (prednisolone and melphalan, to suppress the underlying blood cell dyscrasia). More intensive chemotherapy has a better clinical response, but ther e are few trials. Further Information Falk RH, Raymond L et al. Systemic amyloidosis. NEJM 1997; 337: 898 \200\223908 Gillmore JD, Hawkins PN. Amyloidosis and the respiratory tract. Rare diseases. Thorax 1999; 54: 444 \200\22351 This page intentionally left blank 618 CHAPTER 49 Unusual conditions (BOLD) Hereditary haemorrhagic telangiectasia (HHT; also referred to as Osler \200\223Weber \200 \223Rendu syndrome) Prevalence: 1 in 5000 \200\2238000. De \201 nition An autosomal dominant disorder characterized by the development of abnormal dilated vessels in the systemic circulation, which may bleed leading to: \200 \200 \200 \200 Recurrent epistaxis Gastrointestinal bleeding Iron de \201 ciency anemia Other organ invol vement, e.g. hepatic (in 30%, commonly asymptom- atic), renal, pulmonary, and spinal arteri o venous malformation (AVMs) Screening Careful questioning of family members (Does anyone i n the family have frequent nose bleeds?) and examination for telangiectasia should reveal t hose in whom screening should occur. All those with HHT should be screened for pulmonary AVMs (PAVMs), and all of their offsprin g post-puberty and pre-pregnancy. There is increasing penetrance with increasing age (62% a t age 16, 95% at age 40). Similarly, the detection of PAVMs in a patient should lead to scr eening for HHT in family members. There is no consensus regarding the best screening method, but a com- bination of the following tests may be used: \200 \200 \200 \200 CXR Supine and erect oximetry CT chest Shunt quanti \201 cation techniques, e.g. contrast echocardiogram, 100% oxygen rebreathing Screening should continue throughout life (every 5 \200\22310 years) and during times of en largement or development of AVMs \200\224post-puberty and pre- pregnancy. Management \200 Usually involves liaison with ENT and gastroenterological colleagues for symptomatic treatm ent Iron replacement, transfusions Asymptomatic hepatic AVMs \200\224no treatment usually r equired Cerebral AVMs (in 15% of HHT patients) \200\224some specialists argue these should be treated prophylactically due to the risk of rupture and bleeding (2% per year, often fat al). \200 \200 Further information Shovlin CL, Letarte M. (Hereditary haemorrhagic telangectiasa and pulmo nary AVMs: issues in clinical management and review of pathogenic mechanisms.) Thorax 1999; 54: 714 \200\22339 This page intentionally left blank 620 CHAPTER 49 Unusual conditions (BOLD) Idiopathic pulmonary haemosiderosis A rare disease of undetermined etiology, characterized by recurrent epi- sodes of alveolar hemorrhage and haemoptysis (in the absence of renal dis ease), usually leading to iron de \201 ciency anemia. Pathophysiology The alveolar space a nd interstitium contain haemosiderin-laden macrophages, with variable degrees of interstiti al \201 brosis and degeneration of alveolar, interstitial, and vascular elastic \201 br es, depending on the chronicity of the condition. Electron microscopy shows damage to the e ndothelial and basement membranes, but no consistent or diagnostic features have been recog nized. No antibodies have been identi \201 ed, though serum IgA levels are some- times raised. Wi th recurrent alveolar hemorrhage, the alveolar blood pro- vokes a \201 brotic reaction, w ith the development of diffuse pulmonary \201 brosis. Iron turnover studies show that the accompanying iron de \201 ciency anemia is due to loss of iron into the lung through hemorrhage. Etiology is uncertain, but likely to be multifactorial. Possible associa- tions include toxic insecticides (epidemiolo gical studies in rural Greece), premature birth, and fungal toxin exposure. The disease has an equal sex incidence in childhood, with twice as many men affected in adulthood. Most patients present in childhood, with 85% of cases having onset of symptoms before 16 ye ars. The actual prevalence is unknown, but a cohort study of Swedish children in the 1960s described an incidence of 0.24 per million children. Familial clustering is reported. Pulmonary haemosiderosis is associated with rheumatoid arthritis, thyrotoxicosis, coeliac d isease, and autoimmune haemolytic anemia, sug- gesting a potential autoimmune mechanism. Cl inical features The clinical course is very variable and ranges from continuous low-level b leeding to massive pulmonary hemorrhage. The latter may be fatal, but is fortunately rare. \200 Continuous mild pulmonary hemorrhage leads to a chronic non- productive cough with haemopty sis, malaise, lethargy, and failure to thrive in children Iron de \201 ciency anemia is co mmon, as are positive fecal occult blood tests (due to swallowed blood) Generalized lymphad enopathy and hepatosplenomegaly are recognized. With an acute bleed, cough and haemoptysis may worsen, and dyspnoea, chest tightness, and pyrexia may develop Chronic bleeding leads t o chronic disabling dyspnoea, chronic anemia, and clubbing (in 25%). Cor pulmonale secondar y to pulmonary \201 brosis and hypoxaemia may develop. \200 Examination may be normal. Clubbing, basal crepitations, and cor pul- monale are all recogn ized, depending on the severity of the resulting lung disease. IDIOPATHIC PULMONARY HAEMOSIDEROSIS 621 Investigations The diagnosis is one of exclusion, with no evidence of other organ involveme nt. The main differential diagnosis is Goodpasture \200\231s syndrome, Wegener \200\231s gr anulomatosis, SLE, and microscopic polyarteritis. \200 Blood tests Microcytic, hypochromi c anemia, with low iron levels. ANCA, dsDNA, and anti-GBM antibodies should be negative CXR May show transient patchy in \201 ltrates, which worsen during an acute bleed. The apices are usually spared. Progressive disease leads to the development of reticulonodular in \201 ltrates, and a ground-glass appearance that is typically perihilar or in the lower zon es. Hilar lymph- adenopathy may be seen PFTs kCO is transiently elevated during bleeding ep isodes ( \211 130% is abnormal), but this is only useful acutely. A restrictive defect with reduced kCO may develop with chronic disease CT chest The changes seen are fairly non-spec i \201 c, showing a diffuse bilateral in \201 ltrate, with patchy ground-glass change BAL (if done) contain haemosiderin-laden macrophages. Management There is no speci \201 c treatment. \200 Steroids and immunosuppressive drugs may be of bene \201 t during acute bleeding episodes, but do not appear to affect the long-term outcome. There are no published data to guide th e optimal timing of treatment during the course of disease The iron de \201 ciency anemia responds to replacement therapy, and blood transfusion may be needed in severe bleeds. At routine clinic appointments \200 \200 \200 Check spirometry Measure hemoglobin and serum iron levels Ask about increases in SOB or hae moptysis. Prognosis The prognosis is very variable, with some patients showing spontaneous remission. The duration of disease in the literature ranges from death within days following an acute severe illness, to survival with cor pulmonale associated with chronic disease after 20 ye ars. 622 CHAPTER 49 Unusual conditions (BOLD) Langerhans \200\231 cell histiocytosis De \201 nition Pulmonary Langerhans \200\231 cell h istiocytosis (LCH; previously termed pulmonary histiocytosis X or pulmonary eosinophilic gr anuloma) is a rare condition characterized by in \201 ltration of the lung with histiocyte s (Langerhans \200\231 cells). Pulmonary LCH overlaps with a number of other con- ditions w ith similar pathological \201 ndings but diverse clinical features. These range from loca lized in \201 ltration of a single organ (e.g. eosinophilic granu- loma of bone) to system ic diseases affecting multiple organs (Letterer \200\223 Siwe disease, a multi-organ diseas e affecting infants and elderly, associated with poor prognosis; also Hand \200\223Schuelle r \200\223Christian syndrome). Although the isolated pulmonary form most commonly presents to chest physicians, pulmonary manifestations also commonly occur in the systemic forms of the disease. Epidemiology Rare, it tends to affect young adults aged 20 \200\22340 years. T he vast majority of cases occur in current smokers, usually heavy smokers. May be more comm on in men, who tend to present at a younger age than women. Pathogenesis Langerhans \200 \231 cells are involved in antigen presentation, and are characterized by the presence of w ell-demarcated cytoplasmic organelles called Birbeck granules on electron microscopy. The L angerhans \200\231 cells seen in LCH appear to be monoclonal, although it is unclear if thi s represents a true neoplastic process. The antigen stimulus for activating Langerhans \200 \231 cells in the lung is unknown, although cigarette smoke is a possible candidate. Langer hans \200\231 cells are typically organized into granulo- mata that are located in bronchio lar walls, and subsequently enlarge and invade adjacent structures. This results in the rad iological appearance of nodules that at \201 rst cavitate and then become cystic. Clinica l features Typically exertional breathlessness and cough, some- times with systemic symptom s (e.g. fever, weight loss). Pneumothorax occurs in at least 10% of patients and may be the presenting feature. Rib lesions may also give rise to chest pain. Around 25% of patients a re asymp- tomatic. Examination is usually normal. Investigations \200 CXR Typically diffuse reticulonodular shadowing, sometimes with cystic change; upper and mi ddle lobe predominance. May be normal HRCT Diffuse centrilobular nodules, sometimes with ca vitation, and thin and thick-walled cystic lesions, re \202 ecting lesions of varying age. These are interspersed with normal lung. Upper and middle lobe pre- dominance; costophreni c angles are typically spared. Purely nodular or purely cystic appearances may occur. Unusu al manifestations such as single nodules or large airways involvement are also described PF Ts variable, ranging from normal to obstructive, restricted or mixed patterns. Reduced gas transfer and exertional hypoxia are common TBB may yield diagnostic material, although is o ften unhelpful; risk of pneumothorax is unknown although may be increased. Surgical lung bi opsy is often preferable LANGERHANS \200\231 CELL HISTIOCYTOSIS 623 BAL Increased total cell counts and pigmented macrophages, re \202 ecting simply the prese nce of cigarette smoking. Use of antibodies (e.g. OKT6) to detect Langerhans \200\231 cells in BAL \202 uid is limited by poor sensitivity Extrathoracic biopsy of involved sites (e .g. bone) may be diagnostic Diagnosis Usually based on the combination of clinical and HRCT \201 nd- ings: typically a young adult smoker with cysts and nodules on HRCT. Con \201 rmation by surgical lung biopsy may be considered in atypical presentations, such as the \201 nding of solely nodular or cystic disease on HRCT. The appearance of purely cystic dis ease on HRCT may be confused with emphysema (where cysts lack walls) or lymphangioleiomyoma tosis (where cysts are present uniformly in all regions of lung, including the costophrenic angles). Associations \200 Severe pulmonary hypertension \200\224may be seen in the absence of sig- ni \201 cant pare nchymal lung involvement; direct disease involvement of pulmonary vessels has been describe d Manifestations of systemic LCH \200\224particularly diabetes insipidus from pituitary dis ease, skin involvement, lytic bony lesions, and rarely cardiac or gastrointestinal disease Lymphoma \200\224may precede, complicate, or coexist with pulmonary LCH Lung cancer \200 \224more common, probably as a result of cigarette smoking. Management Treatment other than smoking cessation is often not required. Oral corticosteroids may be tried in symptomatic disease, although there is little evidence to support their use; they are usually administe red for at least 6 months. Lung transplantation should be con- sidered in patients with sev ere respiratory failure or pulmonary hyper- tension. Pulmonary LCH may recur in transplante d lungs. Experimental treatments such as the use of IL-2 and anti-TNFA may be of bene \201 t in the systemic forms of LCH seen in children. Prognosis is variable. Spontaneous improv ement is common, although later reactivation of disease may occur. A minority of patients d eterio- rate rapidly with respiratory failure and death within months. Overall life expecta ncy is reduced, with median survival 12 \200\22313 years from diagnosis. Death is most comm only due to respiratory failure. Poor prognostic factors include reduced FEV1, increased re sidual volume, and reduced gas transfer. \200 Further Information Sundar KM et al. Pulmonary Langerhans \200\231 cell histiocytosis. Ches t 2003; 123: 1673 \200\22383 624 CHAPTER 49 Unusual conditions (BOLD)