Table 16.1.2 Modes of presentation Interstitial lung disease Pneumonitis Fibrosis Eosinophilia Organizing pneumonia Acute respiratory distress syndrome (ARDS) Procainamide Drug-induced lupus often occurs in almost all after 2 years treatment but can occur in up to 33% after 1 year, especially in slow acetylators. Genetic factors have been implicated. Pleural disease Thickening Pleuritis Effusion Pneumothorax Pneumomediastinum Hydralazine Drug-induced lupus occurs in 5 \200\22310%, especially in those >200mg/day, cum ulative dose >100g, female, slow acetyla- tors and having a low C4 complement. Genetic fact ors have also been implicated. Airway disease Direct injury Obliterative bronchiolitis Bronchospasm Bronchial hyper-reactivity (BHR) Pulmonary vascular disease Hemorrhage Infarction Thrombo-embolism Pulmonary hypertension Minocycline Drug-induced lupus often occurs in young women on minocycline for acne. Fever a nd rashes are more common than with other drug-induced cases. Anti-histone Abs are often ab sent (<13%), although p-ANCA (anti-neutrophil cytoplasmic antibodies) may be positive in up to 85%. Infection Pneumonia Aspiration Tuberculosis (TB) CHAPTER 16.1 Drugs and toxins 385 symptoms were not increased lung term or quantities of inhaled B-agonists. Carvedilol has a lso shown to be well tolerated (in terms of FEV1, FEF25-75 and VO2 max) despite being a non -selective B-blocker, possibly because of mild broncho-dilation from its alpha (A)-blocking activity. B-blockers have other (less well known) lung toxicities other than broncho-const riction including pulmonary in \201 l- trates with eosinophilia, hypersensitivity pneumoni tis, organizing pneumonia, \201 brosis, pleural thickening/effusion and drug-induced lupu s. NSAIDs cause bronchoconstriction in 5% of asthmatics by driving cysteinyl leukotriene pr oduction and inhibiting cyclo-oxygenase-1 (COX-1). Key points \200 If both anti-histone Abs and p-ANCA are absent, this makes drug-induced lupus very unlikely . This diagnosis is often forgotten in patients investigated several times for pulmonary em bolism (with negative \201 ndings) and ongoing unexplained pleuritis. If considering hydr alazine-induced lupus, check ANCA as atypical p-ANCA (anti-elastase, not anti-MPO (mye- lop eroxidase)) is speci \201 c for hydralazine-induced vascu- litis and may require immunosup pressant treatment. Table 16.1.4 Discriminating features for drug-induced lupus Drug-induced lupus ACE inhibitors Angiotensin converting enzyme (ACE) inhibitors (ACEI) cause dry nocturnal co ugh in 20% via bradykinin release, normally metabolized by ACE in the lungs. There is a poo r dose response relationship and it usually occurs within 1 month but may take at least 3 m onths to subside after cessation of the drug. The main differentials are usually asthma and heart failure. Gender No female predominance Onset Abrupt Organs involved Less for skin, renal and central nervous system Auto-antibodies 95% anti-histone antibody (Ab) positive Double-stranded deoxyribonucleic acid (dsDNA) Ab ra rely positive AUTHOR \200\231S TIPS \200 Complement Normal B-blockers can be cautiously trialed in mild \200\223moderate reversible obstructive lung d isease. Cardio-selective B-blockers are preferable (atenolol, metoprolol) or combined A- an d B-blockers (carvedilol). Remember other lung toxicities of B-blockers, if bron- cho-const riction does account for the symptoms. Give it 3 months since stopping the ACEI, before ref er- ring or investigating for other causes of chronic cough. Pleural eosinophilia Pleural eosinophilia (>10%) can be due to air or blood in the pleural space, asbestos-related effusion, parasitic infec- tions, but also drugs as listed in Table 16.1.5 below. Table 16.1.5 Common drugs causing pleural eosinophilia. Pleural eosinophilia Nitrofurantoin* Isotretinoin Non-cardiogenic pulmonary oedema ARDS has been associated with a variety of drugs. In over- dose, it has been described with aspirin, cocaine (see later), opioids, phenothiazines and tricyclic antidepressants. At normal doses, nitrofurantoin (see later), protamine and cert ain radiographic contrast media have been implicated. Dantrolene Valproate Propylthiouracil Bromocriptine* Denotes discussed later. AUTHOR \200\231S TIP In ARDS of uncertain etiology, consider drug-related causes especially if psychiatric issues are a possibility AUTHOR \200\231S TIPS \200 The presence of co-existing parenchymal in \201 ltrates would support nitrofurantoin- or b romocriptine-induced lung toxicity amongst this select group of drugs. Concurrent periphera l blood eosinophilia would sup- port nitrofurantoin, dantrolene or valproate-induced lung d isease among this group. Pulmonary arterial hypertension (PAH) PAH has been described in relation to use of anorecti c agents (fex \202 enuramine, dex \202 en \202 uramine) and stimulants including ampheta mines and cocaine. In case control stud- ies, odds ratios of 3 \200\2236 are reported with these agents. The mechanism is uncertain. The anorectics may block potas- sium channels lea ding to calcium in \202 ux increasing pulmo- nary vascular tone. Other studies have report ed a higher prevalence of bone morphogenic protein receptor 2 (BMPR2) mutations in PAH due to anorectic agents. Airway disease b-blockers B-blockers (including eye drops) and cholinergic drugs (e.g. pyri dostigmine) cause bronchoconstriction via bronchial M2-receptor blockade and muscarinic M1 and M3 receptor activation. However, a meta-analysis in reversible obstructive lung dis- ea se has con \201 rmed no evidence of long-term decline in lung function with cardio-selecti ve B-blockers (atenolol, metoprolol). A short-term decline of 8% in FEV1 was seen, but this was not sustained and reversibility of bronchodila- tor increased to about 7%. In addition , respiratory AUTHOR \200\231S TIP In unexplained PAH, drugs must be considered Individual drugs and toxins Amiodarone Amiodarone is one of the commonest drugs implicated ( 5% of patients). Pneumotoxicity is more likely in males, with pre-existing lung disease, at daily doses \211 200mg A MEDFORD 386 (5 \200\22315% chance at \211 400mg), > 2 months treatment, or cumulative doses >150g. The drug is directly cytotoxic but an immunological hypersensitivity also occurs. It has a lon g half-life ( 45 days) and a high af \201 nity for lung tissue. It presents insidiously mo st often as non-speci \201 c interstitial pneumonitis but can present as an organizing pne umonia (25% of cases) or less often (but life threatening) ARDS and rarely as a solitary pu lmonary mass. Foamy lipid macro- phages are present in the airspaces and may be evident on BAL or biopsy but indicate exposure not injury. Lung func- tion is as expected for intersti tial lung disease. There are no predictors for who will develop lung toxicity. Clinical fea tures include dyspnoea, fever, malaise, weight loss with crackles and a high erythrocyte se dimentation rate (ESR), lactate dehydrogenase (LDH) and leucocytosis. Wheeze, pleuritic che st pain and a friction rub may occur. The CXR may show interstitial or alveolar shadowing b ut not pleural effusions. An alternative drug should be used to control arrhythmias if poss ible or reduce dose with steroid cover (prednisolone 40 \200\22360mg od tapering over 2 \200\2236/12). If not, 80% will improve but up to 20% die with respiratory failure. If ARDS devel- ops, mortality is 50%. seen on biopsy. 10% of pneumonitis progresses to pulmo- nary \201 brosis. AUTHOR \200\231S TIPS \200 Exclude infection especially Pneumocystis jiroveci (PCP), cytomegalovirus, fungi, TB and no n-tuberculous myco- bacterium before steroid treatment. Methotrexate lung toxicity is favor ed over rheuma- toid arthritis (RA) itself if biopsy shows granulomas rather than usual int erstitial pneumonia (UIP) and if arthritis quiescent. Bleomycin Life-threatening \201 brosing alveolitis can occur in up to 10% of patients. Bl eomycin hydrolase is not active in the lung (or skin), which may explain toxicity in these tissues although the mechanism is unexplained. Table 16.1.6 shows the factors associated wi th increased lung toxicity. Symptoms and signs are non-speci \201 c and may develop 1 \200 \2236 months following treatment. A more acute hypersensitivity pneumonitis may occur more rapidly. The CXR features are variable, typically nodular but normal in 10%. Pleural effusi ons and adenopathy are rare. BAL is non- specific and sometimes lung biopsy may be needed. Histology resembles diffuse alveolar damage, although organizing pneumonia or eosinophilia pneumonitis may be seen. Steroids may help in pneumonitis with a 50 \200\22370% short- term improvement; the evidence is limited. Steroids should be considered in those with eosinoph ilic pneumonitis or organizing pneumonia. Restarting bleomycin is only possi- ble in those with hypersensitivity pneumonitis. Key points \200 Heart failure is the most important differential and should be suspected and treated if: pl eural effusions, normal ESR, normal gallium scan, abnormal echocardio- gram/pulmonary arter y wedge pressure Consider an alternative anti-arrhythmic before starting amiodarone but if unavoidable, advise patient on poten- tial lung effects, check baseline and serial lung fun ction and aim for maximum 100mg OD maintenance dose BAL is helpful to exclude infection and also makes amio- darone-induced injury unlikely if there are no foamy macrophages Symptoms may progress despite stopping the drug due to accumulation in fatty tissue and long half-l ife AUTHOR \200\231S TIPS \200 \200 Use low inspired oxygen fractions when possible. Consider steroids at 1mg/kg starting dose and taper to clinical response but later relapse may occur. Pulmonary metastases are often the major differential on imaging. Methotrexate Methotrexate pneumotoxicity is also very common, described in 2 \200\2238% of patients, even at doses < 20mg/week. Folic acid supplements do not prevent pneumotoxicity a nd the pathogenesis of lung toxicity remains unclear. Pneumonitis (acute or subacute) devel ops over a 3 \200\2234 year period but most often after a few months treatment, it is often reversible ( 1% mortality). (It has been reported after only day 12 and up to 18 years lat er). Systemic symp- toms may occur before the respiratory symptoms. It may also present as eosinophilia, pleural effusions, organizing pneumonia, ARDS or bronchitis with BHR. Table 1 6.1.6 summarizes factors increasing the chances of lung toxicity. Nitrofurantoin Pneumotoxicity is rare (<1%) but can be severe, usually occurring in women ( because of their greater likelihood of recurrent urinary infection). Acute reactions are mo re common, but sub acute and chronic forms are described. The mechanism of injury in the ac ute form is hypersensitiv- ity leading to eosinophilia, in \202 ammation and microvascular changes. In the more chronic form, an allergic/toxic response is thought to occur with sep tal thickening, \201 bro- sis and organizing pneumonia. It can be associated with ARDS. C linically, fever (>38 C), cough, rash and dyspnoea are the commonest symptoms of the acut e from, typically 9 days after \201 rst exposure (much quicker with subsequent expo- sure s). Eosinophilia, leucocytosis and elevated ESR can occur. The more chronic form develops a fter 1 \200\2236 months with more typical non-speci \201 c symptoms but not fever. CXR cha nges are usually present and BAL may show lym- phocytosis, neutrophilia or eosinophilia. Pl eural eosi- nophilia is also reported. The major differentials here are heart failure and i nfection. Resolution occurs within 48 hours after stopping the drug in the acute form but t akes weeks to 3 months in the less acute forms. The prognosis is very good if detected Table 16.1.6 Factors increasing the risk of lung toxicity with methotrexate and bleomycin Methotrexate Bleomycin Age > 60 Age RA in lung Cumulative dose Previous DMARDs Thoracic radiotherapy Diabetes Renal dysfunction Low albumin High FiO2 BAL tends to show CD4+ lymphocytosis and/or eosi- nophilia. Granulomatous and eosinophilic in \202 ammation is CHAPTER 16.1 Drugs and toxins 387 Penicillamine Bronchiolitis can develop between 3 and 14 months at doses between 375 and 12 50mg. Presentation may be dry cough and dyspnoea with only hyperin \202 ation on the CXR a nd pro- gressive non-reversible air \202 ow obstruction. Mosaicism and air trapping are ev ident on HRCT. Surgical lung biopsy may be needed. Prognosis is poor (50% mortality) and st eroids, cyclophosphamide or azathioprine are often tried. Other less common lung toxicities include pulmonary hemorrhage, drug-induced lupus (see earlier) and pulmonary \201 brosis . early, especially in the acute forms. Sometimes mild \201 brosis persists. AUTHOR \200\231S TIPS \200 \200 There is no evidence to support steroids here. If there is no rapid improvement in 72 hours following stopping the drug in the acute form, the diagnosis may well be wrong. Tumor necrosis factor (TNF) blockers TNF blockers include etanercept (soluble TNF receptor fusion protein), in \202 iximab (dimeric anti-TNF antibody) and adalimumab (anti-TNF monoc lonal antibody). There are case reports of steroid responsive non-caseating granulomatous l ung disease. In addition, there are reports of organizing pneumonia developing in those wit h pre- existing lung disease. More commonly, there is a well-recognized risk of reactiva- t ion of TB most reported with etanercept. The estimated incidence in a large database from 2 000-2001 is 1.1% to 1.9%. Drug-induced lupus is also described (see earlier) with up to nea rly 90% developing positive anti-nuclear antibodies and 14% positive dsDNA antibodies with features of lupus syndrome, including pleuritis in 50%. Le \202 unomide There are reports of accelerated interstitial disease and increases in lun g nodules, but some of this may be due to previous exposure to methotrexate. The nodules st abilize when the drug is stopped. AUTHOR \200\231S TIP Fever, other features of gold toxicity (proteinuria, liver dysfunction , rash, eosinophilia), and absence of clubbing with a lymphocytic BAL would favor pneumonit is due to gold rather than RA Taxanes Paclitaxel can lead to type 1 hypersensitivity reactions with urticaria, bronchospa sm, dyspnoea, hypotension and rash in up to 30% of cases, although steroids and antihistami nes can reduce this to 3%. A type 4 hypersensitivity reaction is also described with both a nd paclitaxel and docetaxel. Acute transient pneumonitis appears usually in the \201 rst 2 weeks after administration. With docetaxel, there are reports of severe and life-threaten ing pneumonitis despite high-dose steroids. The lung effects may be dose-related. As with b leomycin and other agents, concurrent radiother- apy can cause disproportionate toxicity. S equential chest radiotherapy reduces the risk of pneumonitis. Lung toxicity has also been n oted with gemcitabine and taxanes (with- out radiotherapy) in combination in lung and bladd er can- cer, developing over a few days with fever and dry cough but responding to high dos e steroids. AUTHOR \200\231S TIP Consult the British Thoracic Society guidelines for advice on risk ass essment regarding tuberculosis infection before starting TNF blockers: http://www.brit- tho racic.org.uk/c2/uploads/antitnf.pdf Cyclophosphamide This is less common but increased by the use of oxygen, radiation and othe r pneumotoxic drugs. Pneumonitis can occur early or late with \201 brosis. Early pneumoni tis occurs 1 \200\2236 months after onset, with symptoms akin to hypersen- sitivity pneumon itis. Ground-glass change can be a feature. It often responds well to stopping the drug and steroids with complete recovery. Late pneumonitis occurs after several months to years. It presents like UIP, does not respond to steroids and usually leads to respiratory failure i n a chronic and progressive course. It can occur even 6 years after stopping the drug. Hist ology is non-speci \201 c and may mimic UIP or ARDS. Lung biopsy can help in excluding ext rinsic allergic alveoli- tis, infection or diffuse malignancy though. Genetic changes in me tabolism may be important and there is no dose \200\223 response effect. Bloods, and lung f unction abnormalities are non-speci \201 c. AUTHOR \200\231S TIP In lung cancer patients on taxanes 9 gemcitabine, lung toxicity must a t least be considered as respiratory symp- toms will not always be due to infection, the pr imary disease or co-morbid lung disease Mitomycin Table 16.1.7 summarizes the variety of lung toxicities that have been associated with mitomycin. Pre-treatment with steroids can reduce this risk. Bronchospasm can occur in 5%, usually within a few hours and resolving by 24 hours, with/without broncho-dilators. R eticular CXR changes are described and usually resolve. AUTHOR \200\231S TIP CT appearances in the late form of mid-upper region pleural thickening , lack of honeycombing and lack of basal predominance help distinguish it from UIP Table 16.1.7 Mitomycin lung toxicity Bronchospasm Acute pneumonitis Chronic pneumonitis Fibrosis Acute lung injury Pleural disea se \200 \200 \200 \200 \200 Other DMARDs Gold After cumulative exposure >500mg, pneumonitis can occur which responds to stopping the drug and steroids. There are more rare reports of acute respiratory failure, oblitera- tive bronchiolitis and pulmonary \201 brosis. A MEDFORD 388 Acute pneumonitis is characterized by acute dyspnoea that often partially resolves, althoug h 60% can be left with impaired lung function not completely responding to ster- oids. CXR may show focal or diffuse interstitial opacities with physiologically reduced gas transfer and hypoxaemia. In one series, in those receiving thoracic radiotherapy and using oxygen th erapy at an inspired oxygen fraction (FiO2) > 0.5 incurred increased lung toxicity. Chronic pneumonitis seems to be dose related (>30mg/m2). Presentation is usually with insidious dy spnoea and dry cough with nodular appearances on imaging. Clinically and histologically, it resembles bleomycin pneumotoxicity. Lung function tests do not detect early disease and do not pre- dict outcome. Steroids have been used with some success but early relapse after w ithdrawal does occur. Acute lung injury with histological diffuse alveolar damage has been reported which sometimes responds to steroids. Haemolytic uraemic syndrome (with micro-angi opathic haemolytic anemia, thrombocytopaenia, renal impairment, and acute lung injury in 50 %) can occur. It appears to be dose-related and more common if preceding 5- \202 uoro- ura cil or blood transfusions are given. The majority develop this syndrome 6 \200\22312 months after starting treatment. Lowering the dose (<30mg/m2), increasing the dosing interval (>6 weeks) and reducing the FiO2, steroids and plasmapharesis are often tried but mortality re mains high. Pleural exudates and \201 brosis are described often with underlying parencyh mal lung disease. There may be associ- ated lymphocytes and eosinophils. There does not see m to be a dose effect. Histology on TBB and surgical lung biopsy can vary enor- mously. Steroids are not effective in prevention but are used in those with acute respiratory failure or failing to improve a fter stopping the drug despite limited evidence. Prognosis is poor and 52% died in one seri es. AUTHOR \200\231S TIP If pleural effusions and/or mediastinal lymphadenopathy, then an alter native cause should be sought Ergoline drugs Bromocriptine Pleural effusion, thickening and parenchymal changes have been described. Toxicity occurs 1 \200\2234 years after starting the drug. Although pleural eos inophilia is reported, pleural lymphocytosis is more common. Methysergide Extensive pleural \201 brosis can occur with/without effusions. Pleural \201 brosis resolves in most cases where the drug is stopped. Increased serotonin is though t to increase \201 brob- last activity. AUTHOR \200\231S TIP Effusions due to bromocriptine completely resolve on stopping it but t hickening and in \201 ltrates may persist Radiation Haemoptysis, airway disease (bronchitis, obstruction), pleural disease (effusion, pneumothorax), pulmonary vas- cular disease, and parencyhmal lung disease (pneumonitis, pu lmonary \201 brosis) can occur. Pathogenesis may involve cytokines but also hypersensitiv ity. Factors provoking greater lung toxicity are summarized in Table 16.1.8. Injury is dete ctable within hours histologically, but this is asymptomatic. Pneumonitis can occur histolo gi- cally from 3 to 12 weeks, followed by \201 brosis as early as 6 months if there is fa ilure of resolution. Pneumonitis occurs in 5 \200\22315% of patients with lung cancer, with CXR abnormalities in up to 66% although some of these may be related to the primary tumor. Clinical symp- toms may include dry cough, dyspnoea, pleuritic chest pain, low grade fever and malaise. Signs may include crackles or a pleural rub. AUTHOR \200\231S TIP Keep FiO2 <0.3 to minimize acute pneumonitis and acute lung injury wit h sequential rather than concurrent radio- therapy if possible Busulphan Symptomatic injury occurs in 5%. No dose response effect occurs and the histology is variable. However, toxicity seems greater at cumulative doses >500mg. Symptoms include dyspnoea, dry cough, weight loss and fever, typically 4 years after starting the drug but a s early as 8 months sometimes. Basal reticular changes may occur on CXR. Lung function test s do not predict risk. BAL and lung biopsy are usually needed to exclude infection and canc er. Steroids have been tried with variable response but there is a relative lack of evidenc e. Table 16.1.8 Summary of factors provoking greater radiation lung toxicity Factors provoking greater radiation lung toxicity AUTHOR \200\231S TIP Lung toxicity can occur as late as 10 years after exposure to the drug Lung architecture \200\230Serial \200\231: distal from proximal injury Lung volume irradiated >10% Mean dose 20Gy to >35% of lung Chlorambucil Lung disease varies from mild pneumonitis to severe pul- monary fibrosis and t oxicity is not dose dependent. Chronic interstitial pneumonitis is the commonest prob- lem that may occur from \201 ve months to ten years after starting the drug and even several months after stopping the drug. Symptoms may include dry cough, fever, dysp- noea and weigh t loss. Haemoptysis and acute lung injury have been reported. Blood eosinophilia does not o ccur but BAL typically shows CD8+ lymphocytosis and eosinophilia. Imaging typically shows n odules and reticular changes. Lung function tests are as expected for interstitial lung dis ease. Dose fraction Single dose more toxic Chemotherapy Concurrent (sequential less toxic) Other factors Previous chest radiotherapy Smoking Low lung volumes Steroid withdrawal Female The differential is wide and bloods show a non-speci \201 c increased CRP, ESR and LDH. Lu ng function tests are CHAPTER 16.1 Drugs and toxins 389 restrictive but the trend in DLCO may be the most useful predictive measurement. Treatment requires prednisolone 60mg/day for 2 weeks then tapering over the next 12 weeks. Improvemen t does not usually occur beyond 18 months. There is no role for steroids in prophylaxis. Az athioprine or cyclosporin A can be used as steroid-sparing agents based on case reports. In itially promising results with amifostine and captopril have not been replicated. Pentoxify lline is a more promis- ing future candidate. cigarettes daily have the same histological features as tobacco smokers of 20 cigarettes da ily but this may re \202 ect differences in smoking technique (discussed earlier). A proba ble increased risk of chronic obstructive pulmo- nary disease (often with co-existing large bullae) is though to occur. Barotrauma including pneumomediastinum has been reported follo wing Valsava maneuvers and deep inhala- tion leading to alveolar rupture and dissection of air to the mediastinum. Aspergillus contamination of cannabis can lead to allergic bronchop ulmonary aspergillosis (ABPA), or invasive aspergillosis following inhalation. AUTHOR \200\231S TIPS \200 Consider cardiac toxicity from radiotherapy (especially pericardial disease, valvular dysfu nction, coronary artery disease, and cardiomyopathy) as an alternative cause of dyspnoea. S kin erythema outside the port site does not predict the incidence of pneumonitis. A straigh t-line effect on CXR not conforming to normal anatomy and the absence of lymphadenopathy ar e discriminating features. A pleural effusion that is moderate or greater in size and/or in creases in size following observation is unlikely to be due to radiotherapy. AUTHOR \200\231S TIPS \200 Unexplained large bullae with emphysema should prompt enquiry about cannabis (and cocaine). Consider cannabis inhalation in ABPA and invasive aspergillosis. AUTHOR \200\231S TIPS \200 \200 A thorough drug and occupational history is mandatory. A high index of suspicion is needed, check online: http://www.pneumotox.com/ Use online guidelines: http://www.brit-thoracic. o rg.uk/c2/uploads/antitnf.pdf Stop the drug if possible. Exclude infection and heart failure in particular. If the patient fails to respond, reconsider the diagnosis. Cocaine Nearly 25% of cocaine users develop respiratory problems. \200\230Crack lung \200 \231 can occur from 1 \200\22348 hours after smoking: fever, diffuse alveolar shadowing and eosinophilia with his- tology resembling ARDS. Cough, chest pain, dyspnoea and haemoptysis are common. Barotrauma can occur after the smoker performs a Valsalva maneuver (to improve drug delivery) leading to pneumothorax or pneumomediasti- num. Chronic problems can also o ccur with ARDS, organ- ising pneumonia, interstitial pneumonitis and fibrosis, pulmonary in farction or pulmonary artery hypertrophy and hypertension, and severe bullous emphysema. Pu lmonary hemorrhage is also reported. \200 \200 Further reading Albertson TE, Walby WF, Derlet RW. Stimulant-induced pulmonary toxicity. Chest 1995;108:1140 \200\2239. Camus P, Fanton A, Bonniaud P, et al. Interstitial lung disease induced by drugs and radiation. Respiration 2004;71:301 \200\223326. Camus P, Foucher P, Bonniaud P, et al. Drug-induced in \201 ltrative lung disease. ERJ 2001;18:Suppl 32:S93 \200\223100. Costabel U, duBois RM, Egan JJ (eds). Diffuse parenchymal lung disease. Karger, 2007. Foucher P, Biour M, Blayac JP, et al. Drugs that may injure the AUTHOR \200\231S TIPS \200 respiratory system. ERJ 1997;10:265 \200\22379. Consider cocaine toxicity in unexplained bullous emphysema or PAH. If suspected crack lung, consider other adulterant lung toxicities e.g. talc lung. Melanoptysis (carbon residue) an d \201 nger burns (from handling crack pipes) are suggestive. Pulmonary embolic disease i s a major differential. Foucher P, Camus P, GEPPI (Groupe d \200\231Etudes de la Pathologie Pulmonaire Iatrogene). The drug-induced lung diseases. Pneumotox online. http://www.pneumotox.com/ Gotway MB, Marder SR, Hanks DK, et al. Thoracic complications of illicit drug use: an organ system approach. Radiographics 2002;22: S119 \200\22335. Haim DY, Lippmann ML, Goldberg SK, et al. The pulmonary compli- cations of crack cocaine. A comprehensive review. Chest 1995;107:233 \200\22340. Cannabis Up to four times more tar content is inhaled because of different smoking techniqu e, with no \201 lter, greater inhala- tion depth and longer breath hold. In the short ter m, bron- chodilation occurs that diminishes because of tachyphylaxis. Air \202 ow obstruct ion can develop after 8 weeks. Chronic lung toxicity includes a probable increased risk of lung cancer. The absolute excess risk is unknown and co-existing inhaled tobacco smoke may have a role. Bronchial epithelial metaplasia has been demonstrated in humans histologically . Chronic cough, bronchitis, reduced exercise tolerance and reduced lung function occur. Sm okers of 3 \200\2234 cannabis Morelock SY, Sahn SA. Drugs and the pleura. Chest 1999; 116:212 \200\22321. Recommendations for assessing risk and for managing Mycobacterium tuberculosis infection an d disease in patients due to start anti-TNF-a treatment. Joint Tuberculosis Committee of th e British Thoracic Society. Thorax 2005; 60: 800-805. h t t p : / / w w w . b r i t - t h o r a c i c . o r g . u k / c 2 / uploads/antitnf.pdf Reed CR, Glauser FL. Drug-induced noncardiogenic pulmonary oedema. Chest 1991;100:1120 \200\22324. Tashkin DP. Pulmonary complications of smoked substance abuse. West J Med 1990;152:525 \200\22330. Whitcomb ME. Drug-induced lung disease. Chest 1973;63:418 \200\22322. I COUTTS 390 16.2 Pneumoconiosis The International Labor Of \201 ce (ILO) Classi \201 cation of Radiographs has been used to describe the profusion and type of radiographic opacity in pneumoconioses. The pro- fusi on of small opacities is categorized as follows: \200 Pneumoconiosis is a term covering a group of dust-associated diseases of the lung. The main individual diseases are coal workers pneumoconiosis, silicosis and asbestosis. Parkes sugg ests that pneumoconiosis may be defined as the non-neoplastic reaction of the lungs to inha led mineral or organic dust and the resultant alteration in their structure but excluding a sthma, bronchitis and emphysema. This section will deal with pneumoconiosis caused by inor- ganic dusts only and will exclude asbestosis, which is dealed with elsewhere. Category 1 indicates the presence of small opacities which are few in number. Category 2 in dicates the presence of numerous small opacities but where the normal lung markings are sti ll visible. Category 3 indicates very numerous small opacities which partially or totally o bscure the normal lung markings. Epidemiology With improved occupational hygiene and the decline of the coal mining industry pneumoconioses caused by inor- ganic dust exposure should become diseases of the past. Fig . 16.2.1 shows the number of cases being compensated annually for pneumoconiosis other than asbestosis. Most cases occur in retired coal workers. A smaller number arise in quarry and foundry workers and in the potteries where silica was the main cause. The recent increase in cases is probably due to more accu- rate recording and a publicity campaign in 2002. Dea th from pneumoconiosis is on a long-term downward trend. The small opacities are usually rounded in coal workers pneumoconiosis and silicosis and ar e graded by size. \200 \200 \200 \200\230p \200\231 describes opacities upto about 1.5mm. \200\230q \200\231 describes opa cities between 1.5mm and 3mm. \200\230r \200\231 describes opacities between 3mm and 10mm. Large opacities (see Fig. 16.2.2) are categorized as A, B or C as follows: \200 Category A \200\223 an opacity with a greatest diameter between 1cm and 5cm or several opa cities each greater than 1cm, the sum of whose greatest diameters does not exceed 5cm. Cate gory B \200\223 one or more opacities larger than those in Category A whose combined area does not exceed the equivalent of the right upper zone. Category C \200\223 one or more op acities whose combined area exceeds the equivalent of the right upper zone. Cases 1200 1000 800 600 400 200 0 1982 1984 1986 1994 1990 Silicosis or unspecified pneumoconiosis Coalworkers \200\231 pneumoconiosis Deaths 1998 2000 2002 2004 1988 1992 1996 } Disablement benefit (MS) cases Fig. 16.2.1 Pneumoconiosis (other than asbestosis). Diagnosis The diagnosis of pneumoconiosis depends on three things: \200 \200 \200 A high quality chest radiograph. A complete occupational history. Clinical examination. The importance of a complete occupational history includ- ing every job since leaving schoo l cannot be over empha- sised, particularly as the relevant dust exposures are likely to ha ve occurred many years ago. Fig. 16.2.2 Progressive massive \201 brosis in a coal miner. Radiology Pneumoconioses give rise to small round or irregular opacities on the CXR. In mor e severe cases of coal work- ers pneumoconiosis and silicosis large opacities can develop b ut these are not seen in asbestosis. Coal workers pneumoconiosis and silicosis give rise to predominantly round opacities situated in the middle and upper zones whereas asbestosis ma nifests with small irregular opacities at the lung bases. Small irregular opacities are designated \200\230s \200\231, \200\230t \200\231 and \200 \230u \200\231. Standard films are available to guide classification for epidemiological pu rposes. Coal workers pneumoconiosis This disease is caused by inhaling coal mine dust and its devel opment is mainly dependent on the mass of respira- ble dust to which the miner has been exp osed. CHAPTER 16.2 Pneumoconiosis 391 Pathology Dust particles arriving in the alveoli are phagocytosed by macrophages and transp orted proximally to the respira- tory bronchioles and the mucociliary escalator. When this system is overwhelmed dust laden macrophages accumu- late near the center of the secondary pulmonary lobule. Reticulin and later collagen are deposited in these macules giving rise t o the discrete \201 brotic lesions which constitute simple pneumoconiosis. In the case of coal workers pneumoconiosis collagen deposition is usually minimal. Complicated pneumoconi osis or progressive massive \201 brosis occurs when large opacities develop. These usuall y occur only in miners with well developed (category 2 or 3) simple pneumoconiosis. These l esions may cavitate. Multiple well de \201 ned round opacities 0.5 \200\2235cm in diameter and distributed throughout the lung \201 elds were observed by Caplan in miners with or who subsequently developed rheumatoid arthritis. The lesions tended to develop rapidly ofte n against a background of minor simple pneumoconio- sis and the lesions could cavitate. Thi s pattern of disease is referred to as Caplan \200\231s syndrome. Silicosis Silicosis is probably the oldest pneumoconiosis to af \202 ict man. Dusty trades have been associated with ill health since antiquity but silicosis should now be a disease of the past. Silica exposure occurs in: \200 \200 \200 \200 Quarrying of slate, granite and sandstone. Hard rock mining. Tunneling. Foundry work where silica was used in molds and cores. Pottery and ceramic industries. Occasional cases of silicosis are still reported often where workers have been exposed to s ilica by new industrial processes where the silica risk had not been appreciated. Pathology Silicosis is caused by inhaling crystalline silica dust. The prevalence and sever ity of disease is largely determined by the intensity of exposure. Silica excites a more \202 orid \201 brotic reaction than coal mine dust. This leads to palpable nodules compos ed of concen- tric layers of \201 brous tissue which may coalesce to produce massive \201 brosis with associated distortion of lung architec- ture and scar emphysema. Signs and symptoms Simple coal workers pneumoconiosis does not give rise to any signs or sy mptoms. The early stages of complicated coal workers pneumoconiosis (Category A) is usually symptomless, but more advanced disease can lead to respi- ratory disability which may be s evere. Melanoptysis, the production of black sputum, can occur if an area of massive \201 brosis cavitates. Coal dust can become incorporated into healing skin abrasions and thereb y give rise to a form of tattooing. This is not particularly associ- ated with pneumoconios is but if observed should serve as a prompt for a full occupational history. Radiology The nodules in silicosis tend to be denser and larger than those in coal workers pneumoconiosis and affect predomi- nantly the upper lobes (see Fig. 16.2.3). Eggshell calci \201 cation of hilar lymph nodes can occur. Lung function testing Simple pneumoconiosis has little effect on lung function. Complicated pneumoconiosis especially categories B and C lead to abnormalities of lung function which are poorly correlated with radiographic appearances. Decline may be found in FEV1, and FVC often with an obstructive pattern. Total lung capacity and gas transfer are usually reduced . Prognosis Simple coal workers pneumoconiosis and Category A complicated pneumoconiosis do n ot shorten life. Complicated coal workers pneumoconiosis of Categories B and C is associate d with increased mortality mainly in association with air \202 ow obstruction. Fig. 16.2.3 Silicosis in a granite quarry worker. Differential diagnosis Simple coal workers pneumoconiosis may be confused with: \200 \200 \200 Sings and symptoms Early disease is usually symptomatic. Cough and breath- lessness occur a s the disease progresses and in severe cases respiratory failure may occur. There are no si gns that are speci \201 c to silicosis. Finger club- bing does not occur. Sarcoidosis. Miliary tuberculosis. Extrinsic allergic alveolitis. Complicated coal workers pneumoconiosis may be confused with: \200 Lung cancer. \200 Pu lmonary metastases. \200 Sarcoidosis. \200 Tuberculosis. \200 Wegener \200\231s granu lomatosis. Lung function Small reductions in vital capacity may occur in simple silicosis. As the dise ase advances there is a decrease in TLC, VC, RV, FRC and there may be evidence of airways o bstruction. I COUTTS 392 Compilications \200 Mixed dust \201 brosis This disease occurs when the effects of silica are modi \201 ed b y accompanying non- \201 brogenic dusts. It has been seen in haematite miners and in found ry workers. It gives rise to an irregular \201 brotic upper lobe disease which radiograph ically resembles \201 brocaseous tuberculosis. The lesions do not calcify nor is eggshell calci \201 cation seen. Tuberculosis \200\223 silicosis predisposes to tuberculosis and in the past silicotubercul osis often lead to death. Environmental mycobacterial infection. Emphysema. Spontaneous pne umothorax. Cancer of the lung. Hard rock miners exposed to silica are often exposed to rado n which is a known lung carcinogen but there is increasing concern that silica itself may b e a lung carcinogen. \200 \200 \200 Kaolinosis Heavy exposure to kaolin (china clay) occurred in certain types of clay drying p rocesses and could lead to a simple pneumoconiosis and very rarely to complicated pneumo- c oniosis. Simple pneumoconiosis cause by kaolin in the UK did not appear to cause symptoms o r shorten life. Prognosis Uncomplicated silicosis does not usually shorten life but may do so if supervenin g tuberculosis is not diagnosed and treated promptly. Complicated silicosis can lead to res piratory failure and thereby shorten life. Talc Talc has been used as a lubricant in the rubber industry and in roof felting. Talc has a precise mineralogical de \201 nition but the term has been used loosely in industry. Co mmercial talc often con- tained impurities including signi \201 cant amounts of quartz and asbestos minerals. It is unclear whether pure talc causes a pneumoconiosis but contaminate d talc has given rise to pneumoconiosis with patterns similar to silicosis, asbestosis or c ombinations of the two diseases. Differential diagnosis \200 \200 \200 \200 Sarcoidosis. Metastases. Lung cancer. Wegener \200\231s granulomatosis.