CHAPTER 8 Pleural effusion 50 Exudative pleural effusions Mechanisms involve an increase in capillary permeability and im paired pleural \202 uid resorption. Differential diagnosis Table 8.2 Causes of exudative pleural effusions. Cause Notes Common Parapneumonic effusion Occurs in 40% of bacterial pneumonias; commonest exudative effusion in young patients (p 420) Malignancy Commonest exudative effusion in patients >60 years (p 279) Pulmonary embolism 80 \200\22390% are exudates (p 401) Rheumatoid arthritis Typically low pleural \202 uid glucose, often <1.6 mmol/L (p 188) Mesothelioma Pleural \202 uid cytological analysis has low sensitivity (p 114) Less common Empyema Pleural \202 uid pH <7.2; clinical features of infection, e.g. fever, sweats (p 352) Tuberculosis Typically lymphocytic effusion; pleural \202 uid AFB smear positive in 10% of cases, cult ure positive in 25%, Abrams \200\231 biopsy histology sensitivity 90% (p 490) Other infections Very rare; include viral, parasitic, rickettsial, and fungal (e.g. aspergillus, histoplasma , coccidioidomycosis) Hepatic, splenic, or subphrenic abscess Oesophageal rupture Initially sterile exudate, followed by empyema; pH <7.2, raised salivary amylase, often his tory of vomiting Pancreatitis Pleural \202 uid pancreatic amylase may be raised SLE Lupus erythematosus cells in \202 uid are diagnostic; may respond quickly to prednisolone Other autoimmune diseases Churg \200\223Strauss syndrome (intensely eosinophilic \202 uid), Sj gren \200\231s synd rome, scleroderma, dermatomyositis, Wegener \200\231s granulomatosis Sarcoidosis Effusions are uncommon Pleural effusions common; may be blood-stained Post-cardiac injury syndrome (Dressler \200\231s syndrome) Post-coronary artery bypass surgery (p 361) EXUDATIVE PLEURAL EFFUSIONS 51 Table 8.2 Causes of exdative pleural effusions (cont.) Cause Notes Less common Radiotherapy May cause small, unilateral effusions up to 6 months after treatment Uraemia Effusions frequently resolve after starting dialysis Chylothorax Presence of chylomicrons or pleural \202 uid triglyceride level >110 mg/dl (p 55) Benign asbestos-related pleural effusion (p 110) Drug-induced Drugs include amiodarone, bromocriptine, methotrexate, phenytoin, and nitrofurantoin; see w ww. pneumotox.com for full list; effusions usually resolve following discontinuation of dru g Other, rare causes Include yellow nail syndrome, cryptogenic organizing pneumonia, amyloidosis, familial Medit erranean fever Treatment of exudates involves treatment of the underlying cause, as well as measures to im prove breathlessness and remove pleural \202 uid, e.g. therapeutic thoracentesis (p 783), intercostal drainage (p 760), and pleurodesis (p 776). 52 CHAPTER 8 Pleural effusion Pleural \202 uid analysis 1 \200\230Routine \200\231 pleural \202 uid analysis compris es assessment of: \200 \200 \200 Pleural \202 uid appearance Biochemistry (protein and LDH) Cytology (for malignant cells and differential cell count; ideally fresh 20-mL sample) Microbiology (Gram stain and micro scopy, culture, and AFB stain and culture; inoculation of blood culture bottles with pleura l \202 uid may increase yield) pH Although considered routine, some of these investigations may be unnecessary and even misle ading, depending on the clinical picture (e.g. microbiological analysis on patients suspect ed as having transudates). Additional pleural \202 uid investigations such as measurement of cholesterol and triglyc erides, haematocrit, glucose, and amylase may be helpful in certain clinical circumstances. PLEURAL FLUID ANALYSIS 1 53 Appearance Appearance Possible causes Bloody Trauma, malignancy, pulmonary infarction, pneumonia, post-cardiac injury syndrome, pneumoth orax, benign asbestos-related pleural effusion, aortic dissection/ rupture; de \201 ned as haemothorax if pleural \202 uid haematocrit >50% of peripheral blood haematocrit (p 360) Turbid or milky Empyema, chylothorax, pseudochylothorax (clear supernatant after centrifuging favors empyem a; cloudy after centrifuging suggests chylothorax or pseudochylothorax, p 55) Putrid odor Anaerobic empyema Viscous Mesothelioma Food particles Oesophageal rupture Urine odor Urinothorax Black Aspergillus infection Brown, \200\230anchovy sauce \200\231 Amoebic liver abscess draining into pleural space Differential cell count Predominant cell type Possible causes Neutrophils Any acute effusion, e.g. parapneumonic, pulmonary embolus Mononuclear cells Any chronic effusion, e.g. malignancy, tuberculosis Lymphocytes Tuberculosis, especially if over 80%; other causes include malignancy, sarcoidosis, lymphom a, rheumatoid pleurisy, post-CABG Eosinophils Often unhelpful; associations include air or blood in pleural space (haemothorax, pulmonary infarct, pneumothorax, previous tap), malignancy, infection (parapneumonic, tuberculous, f ungal, parasitic), drug- and asbestos-induced effusions, Churg \200\223Strauss syndrome or idiopathic Mesothelial cells Predominate in transudates; variable numbers in exudates, typically suppressed in in \202 ammatory conditions, e.g. tuberculosis Lupus erythematosus cells Diagnostic of systemic lupus erythematosus 54 CHAPTER 8 Pleural effusion Pleural \202 uid analysis 2 Pleural \202 uid pH and glucose Pleural \202 uid pH may b e measured using an arterial blood pH analyzer. The sample should be appropriately heparini zed, e.g. aspirate a few mL of pleural \202 uid into a pre-heparinized blood gas syringe. Frankly purulent samples should not be analyzed \200\224it is unnecessary, and might damag e the machine. Normal pleural \202 uid pH is about 7.6. An abnormally low pH (<7.3) suggests pleural in \202 ammation and is often associated with a low pleural \202 uid glucose (<3.3 mmol/L o r pleural \202 uid/serum glucose ratio <0.5). The mechanism probably involves increased n eutrophil phagocytosis, and bac- terial or tumor cell breakdown, resulting in the accumulat ion of lactate and carbon dioxide. Causes of low pH and low glucose effusions \200 Parapneumonic effusion and empyema (pH <7.2 indication for drainage of pleural space, as un likely to resolve spontaneously) Rheumatoid pleuritis (glucose <1.7 mmol/L in 66% and <2.8 mmol/L in 80% of cases) Malignant pleural effusion (associated with advanced disease and po or survival, higher sensitivity of pleural \202 uid cytological analysis, and failure of pleurodesis) Tuberculous pleural effusion Oesophageal rupture Lupus pleuritis. \200 \200 Urinothorax is the only transudative effusion that can cause a pH <7.3. An abnormally high (alkaline) pH may rarely occur in the setting of Proteus pleural infection. Pleural \202 uid triglyceride and cholesterol Measure in turbid or milky effusions or where chylothorax is suspected. Chylothorax occurs following disruption of the thoracic duct, and pleural \202 uid may ap pear turbid, milky, serous, or blood-stained. The presence of pleural \202 uid chylomicro ns or a pleural \202 uid triglyceride level >110 mg/dl con \201 rms the diagnosis. Cause s of chylothorax: \200 \200 \200 \200 Malignancy (particularly lymphoma) Trauma Following thoracotomy Pulmonary lymphangioleiomyo matosis. Pseudochylothorax occurs due to cholesterol crystal deposition in chronic effusions, most c ommonly due to rheumatoid pleurisy or tuberculosis, and may cause a milky effusion; raised pleural \202 uid cholesterol (>200 mg/dl) and cholesterol crystals at microscopy distingu ish it from chylothorax. PLEURAL FLUID ANALYSIS 2 55 Pleural \202 uid amylase Abnormal if pleural \202 uid amylase > upper normal limit for serum amylase, or if amylase pleural \202 uid/serum ratio >1.0. Causes include: \200 Pleural malignancy and oesophageal rupture (both associated with raised salivary amylase) P ancreatic disease (acute and chronic pancreatitis, pancreatic pseudocyst; associated with r aised pancreatic amylase). NB. May be normal early in the course of acute pancreatitis or oesophageal rupture. This page intentionally left blank 57 Chapter 9 Post-operative breathlessness CHAPTER 9 Post-operative breathlessness 58 The respiratory physician is often asked to see patients post-operatively who have become d yspnoeic following an operative procedure. The risk of pulmonary complications is greatest with thoracic or upper abdominal surgery, when a degree of pulmonary dysfunction and conseq uent breath- lessness due to atelectasis is inevitable. Always rule out upper airway obstru ction. The four most likely common causes are: \200 \200 \200 \200 Infection/atelectasis Pulmonary emboli Left ventricular failure ( \202 uid overload) Exace rbation of underlying lung disease, such as COPD or UIP. Points to consider when assessing these patients \200 Is the patient acutely unwell, needing immediate resuscitation and ventilatory support? Com orbid disease and past medical history, especially pulmonary, cardiac, or thromboembolic di sease Type of surgery \200 Thoracic surgery: consider lobar gangrene (torsion of the remaining lobe causing vascular o cclusion) leading to pulmonary infarction with fever and haemoptysis, bronchopleural \201 stula, often associated with an infected pleural space, leading to sepsis and failure of t he underlying lung to re-expand Time since surgery: \200 Early complications (hours) related to residual anesthetic effect not adequately reversed, atelectasis, respiratory failure, hypovolaemic shock, infection, PE, fat embolism, air embo lism, left ventricular failure and \202 uid overload, myocardial ischaemia Later complica tions (hours \200\223days) related to PE, ARDS, infection, myocardial ischaemia. Initial tests to consider performing in these patients \200 Oxygen saturations and arterial blood gas breathing room air and on oxygen ECG CXR \200\224 compare with pre-operative CXR, if available Full blood count and clotting screen U&E and b icarbonate See if they had pre-operative oximetry and spirometry performed. There should be a record of the oxygen saturation in the anesthetic room. \200 \200 \200 \200 A D-dimer level is unhelpful as it will be raised by many different intra- and post-operati ve mechanisms. CRP and WCC are also largely unhelpful as these are frequently raised post-operatively. POST-OPERATIVE BREATHLESSNESS 59 Table 9.1 Assessment of dyspnoea Possible cause of dyspnoea Management options Adequate analgesia to encourage expectoration, nebulized saline, chest physiotherapy, deep breathing. If lung does not rein \202 ate, consider bronchoscopy to suction out secretions Basal atelectasis (commoner in smokers and following abdomi- nal or trans-thoracic proce- d ures. Mucus in bronchial tree causes small airway obstruc- tion, subsequent alveolar air re absorption, and collapse of lung segments); collapsed lobe \200\224mucus plugging If fever and chest signs, give antibiotics for hospital-acquired pneumonia (see p 436), ade quate analgesia to encourage expectoration, chest physiotherapy Oxygen as required. Measure A \200\223a gradient on blood gas. Start treatment dose of unfractionated heparin (if not contraindicated by the operation), arrange VQ scan or CTPA, check D-dimers (although unhelp ful unless negative). If in extremis consider urgent CT or echocardiogram and thrombolysis (see p 401) Opiate overdose or anesthetic agents causing neuromuscular block not reversed. Undiagnosed respiratory muscle weakness Check U&E, look for underlying problem, such as ren al failure or sepsis Oxygen, check cardiac enzymes and 12-h troponin. Sublingual or IV glyc eryl trinitrate if required for pain. Start prophylactic heparin (if not contraindicated by the operation) Thrombolysis likely to be contraindicated by recent surgery, so consider re ferral for primary angioplasty. Consider aspirin, clopidogrel, low molecular weight heparin Pneumonia \200\224follows atelectasis and collapse. Possible aspiration also Thromboembolic disease Respiratory failure Metabolic acidosis Myocardial ischaemia Myocardial infarction or acute coronary syndrome Cardiac failure/ \202 uid overload Oxygen, IV furosemide, central line, and ionotropes if required. Echocardiogram to assess left ventricle Supportive, likely to need mechanical ventilatory assistance (see p 101) Diagnose on lung function tests, CXR, and clinically dec reased diaphragm movement. Advise to tilt whole bed (head up) when sleeping. Phrenics may r ecover, but can take 2+ years Oxygen, IV \202 uids, supportive care ARDS Phrenic nerve damage causing diaphragmatic paralysis. May occur with thoracic operations su ch as CABG Fat embolism following long bone fracture, especially with reaming and manipulat ion Laryngeal spasm Anemia Reassurance, oxygen if required Cross-match and transfuse. Identify if ongoing bleeding sou rce May need intubation and ventilation. Stop all anti-cholinesterases. Consider plasma exc hange and IV immunoglobulin. Urgent neurology input Myasthenia gravis crisis precipitated by anesthetic agents This page intentionally left blank 61 Chapter 10 Pregnancy and breathlessness Causes 62 Investigations 64 CHAPTER 10 Pregnancy and breathlessness 62 Causes Normal physiological changes of pregnancy \200 Elevated serum progesterone levels stimulate respiratory drive and lead to an increased tid al volume and raised minute ventilation, with only a modest increase in oxygen consumption. The subsequent fall in maternal pCO2 facilitates fetal CO2 transfer across the placenta; a ny cause of maternal hypercapnia leads quickly to fetal respiratory acidosis. Respiratory r ate is unaffected by pregnancy. Elevation of the diaphragm occurs due to the enlarging uter us, leading to a reduced functional residual capacity, although diaphragm function is norma l and vital capacity is unaffected. Peak \202 ow and FEV1 are unaffected by pregnancy Inc reased cardiac output occurs due to an increase in heart rate (by about 15 beats/min) and s troke volume; peripheral resistance falls. Blood pressure is reduced in the \201 rst and second trimesters by 10 \200\22320 mmHg, but is normal at term. Peripheral pulses tend to b e increased in volume. Dependent oedema is common. Third heart sound and ejection systolic murmurs are commonly heard. May hear venous hums in the neck Raised levels of coagulation f actors and impaired \201 brinolysis, combined with venous stasis, result in a 5-fold incr eased risk of venous thromboembolism Upper airway oedema, particularly in the setting of pr e-eclampsia, may predispose to upper airways obstruction during sleep, but rarely frank obs tructive sleep apnoea. OSA tends to occur in obese women, and may be associated with impair ed fetal growth and pre-eclampsia. Snoring in pregnancy is a poor predictor of OSA. Causes of breathlessness in pregnancy Causes are listed in the box opposite. In general, br eathlessness may be due to: \200 Normal physiological changes of pregnancy. Up to 75% of pregnant women experience a degree of breathlessness, perhaps as a result of the increase in ventilation. Tachypnoea is a usef ul sign, as it is abnormal in pregnancy and suggests an underlying disease process New dise ase process. Pulmonary embolism is the commonest and is a major cause of maternal death. Ot her rare, but serious, causes include amniotic \202 uid embolism and ARDS Exacerbation of chronic respiratory or cardiac disease. Asthma is the commonest. Unsuspected underlying di sease may present for the \201 rst time in pregnancy, e.g. structural heart disease such as mitral stenosis, lymphangioleiomyomatosis. Pulmonary hypertension is associated with a p articularly poor prognosis during pregnancy. Patients with interstitial lung disease and vi tal capacity <1 L should also consider avoiding pregnancy. In patients with cystic \201 b rosis, the presence of pulmonary hypertension or FEV1 <50% predicted are associated with a poor outcome. CAUSES 63 Causes of breathlessness in pregnancy Pulmonary \200 Exacerbation of pre-existing lung disease, e.g. asthma (p 140), cystic \201 brosis, lymph angioleiomyomatosis Pneumonia (p 419) \200 Bacterial: usual organisms, including tuberculosis (p 502) and aspi- ration (p 442) Viral: particularly varicella, in \202 uenza (p 538, 532) Fungal: particularly coccidioidomycosis (p 483) \200 Aspiration pneumonitis Pulmonary metastases from choriocarcinoma (very rare). \200 Pleural \200 \200 \200 Pneumothorax (p 373), particularly during labor Small asymptomatic effusions post-partum Ov arian hyperstimulation syndrome (very rare). Vascular \200 \200 \200 \200 Pulmonary embolism (p 401) Amniotic \202 uid embolism (p 416) Air embolism (p 416) Pulmon ary hypertension (p 385). Cardiogenic pulmonary oedema \200 \200 Exacerbation of pre-existing cardiac disease, e.g. mitral stenosis Peripartum cardiomyopath y. Non-cardiogenic pulmonary oedema \200 \200 Iatrogenic \202 uid overload Tocolytic therapy ( \237-agonists used to inhibit uterine co ntractions in preterm labor) ARDS due to pre-eclampsia, sepsis, massive hemorrhage, amnioti c \202 uid embolism. Other \200 \200 \200 Anemia Oesophageal rupture Hemidiaphragm rupture. CHAPTER 10 Pregnancy and breathlessness 64 Investigations Liaise with your obstetrics team, as well as with pediatricians and anaes- t hetists, if delivery is approaching. Management of speci \201 c conditions is discussed in the individual disease chapters in Part 2. The following investigations may be affected by the pregnancy itself: ABGs. Normal maternal pO2 >13.3 kPa and pCO2 3.7 \200\2234.3 kPa. A compensatory fall in serum bicarbonate (to 1 8 \200\22322 mmol/L) occurs, resulting in an average pH of 7.44. During the third trimester , perform ABGs in an upright position, as pO2 may be 2.0 kPa lower when supine. A \200\223a gradient is unaffected during pregnancy, except when supine near term Blood tests. In norma l pregnancy, WCC, platelets, ESR, D-dimers, and \201 brinogen are usually raised, and ser um creatinine levels reduced. CRP is not signi \201 cantly affected. D-dimer is increased from about 6 weeks gestation to 3 months post-partum CXR may show increased pulmonary vascu lature due to normal increase in cardiac output. Required for diagnosis of pneumonia and pn eumothorax. With abdominal shielding, the radiation doses to mother and baby are very small and CXR should be performed if clinically necessary. Lateral CXR carries a greater radiati on exposure and should be avoided Ventilation \200\223perfusion scans are considered relati vely safe in pregnancy, and are the investigation of choice if pulmonary embolism is suspec ted (although some experts suggest performing leg vein ultrasound \201 rst; if an asympto matic DVT is con \201 rmed in the setting of clinical features suggestive of pulmonary emb olism, then treatment may be started without the need for radiation exposure from further i maging). If V/Q is non-diagnostic, consider pulmonary angiography; the radiation exposure f rom the combination of CXR, V/Q, and angiography is not thought to be associated with fetal injury. CT pulmonary angiography carries a greater radiation dose and, in the setting of t he hormonal changes within the breast during pregnancy, leads to an increased risk of breas t cancer in the mother. 65 Chapter 11 Pre-operative assessment CHAPTER 11 Pre-operative assessment 66 The respiratory physician may be asked to assess a patient prior to elective or emergency s urgery. These patients are usually those with pre-existing respiratory disease, such as COP D. \200 \200 The usual functional status of the patient should be determined Their respiratory function should be optimized if possible, with medica- tion changes where appropriate. These patients may require ventilatory support post-operatively. Ultimately the decisions r egarding \201 tness for surgery rest with the surgeon and the anesthetist. Assessing the pre-operative patient \200 Usual functional state and exercise tolerance (those with an exercise tolerance of <5 m wil l not come off a ventilator) Oxygen saturations on air and after exertion, such as walking or climbing up and down a step for 2 min Arterial blood gas on air, if saturations <94%. Ri sk of surgery increases as the CO2 increases Spirometry, with bronchodilator reversibility testing. Risk of surgery increased if FEV1 <0.8 L CXR \200\224if 65+ and no CXR in last yea r, or if acute respiratory symptoms History of snoring or OSA ECG Echocardiogram, if cardia c function compromised. \200 \200 \200 Options for management of the pre-operative patient \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 Regular inhaled or nebulized bronchodilators, if air \202 ow obstruction Regular inhaled steroid, if evidence of steroid reversibility Pre-operative course of oral steroids, if evi dence of steroid reversibility Pre-operative course of antibiotics, if evidence of infectio n Consider pulmonary rehabilitation Consider chest physiotherapy with deep breathing exerci ses Referral for CPAP if OSA present Optimize nutrition Lose weight Advise to stop smoking \200\224ideally 8 weeks prior to surgery; reduces post-operative complication rate. Risk factors for peri-operative complications \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 Thoracic or upper abdominal surgery Anesthetic length >3.5 h Smoker Chronic lung disease Ra ised PaCO2 Current respiratory symptoms Poor performance status Concurrent cardiac disease Obesity Older age. 67 Chapter 12 Pulmonary disease in the immunocompromised (non-HIV) Clinical assessment 68 Further investigations 70 Causes 72 Differential diagnosis of pulmon ary complications based on time course after transplantation 74 Treatment 76 CHAPTER 12 Pulmonary disease (non-HIV) 68 Clinical assessment Respiratory disease is a signi \201 cant cause of morbidity and mortal ity in the immunocompromised, and its diagnosis and management are challenging. In the UK t his is encountered most commonly in the setting of immuno- compromise secondary to cytotoxi c chemotherapy, hematological malignancy, immunosuppression post-transplant (particularly r enal and haematopoietic stem cell transplant [HSCT, including bone marrow, fetal cord blood , and growth-factor-stimulated peripheral blood transplanta- tion]), prolonged corticostero id use, and AIDS (p 79). Most pulmonary diseases present in a similar manner in the setting of immunocompromise, wit h fever, dyspnoea, dry cough, chest pain, and often hypoxia. This non-speci \201 c clinica l presentation, combined with the large number of possible causes, makes reaching a precise diagnosis dif- \201 cult; the diagnosis remains unclear in up to 10% of cases even at au topsy. There is limited evidence to demonstrate that obtaining a de \201 nitive diag- nosi s leads to an overall improvement in mortality, although, in subgroups such as patients wit h respiratory infection, early identi \201 cation and treat- ment of pathogens has been sh own to improve outcome. Causes of pulmonary in \201 ltrates in the non-HIV-infected immunocom- promised are presen ted on p 72, and treatment on p 76. Speci \201 c con- ditions are described separately (e. g. invasive aspergillosis, p 470; PCP, p 476). Key steps in the management of these patients are as follows. Clinical assessment In the history, the underlying cause of immuno- compromise and the timi ng and location of respiratory disease onset may provide clues to the diagnosis. The rate o f disease onset may also suggest possible causes: \200 Acute onset (<24 h) Bacterial pneumonia, viral pneumonitis (e.g. CMV), pulmonary oedema or hemorrhage, pulmonary emboli, ARDS Subacute onset (days) Fungi (e.g. Pneumocystis, Aspergil lus), bacteria (e.g. Nocardia, Legionella), viral (e.g. CMV), drug-induced pneumonitis Chro nic onset (weeks) Malignancy, mycobacteria, fungi. Chest examination may suggest the extent of pulmonary involvement, although this can be mis leading and there are often no abnormal signs (e.g. PCP, or bacterial pneumonia in the sett ing of neutropenia). Assess \202 uid status; pulmonary oedema is common following transpl antation. Extrapulmonary involvement may be helpful in suggesting a pathogen, e.g. cutaneou s lesions (herpes simplex and varicella-zoster; necrotic lesions from Pseudomonas and other Gram-negative bacteria, mycobacteria, and fungi; subcutaneous abscesses in Staphylococcus aureus and Nocardia), central nervous system involvement (Pseudomonas, Aspergillus, Cryptoc occus, Nocardia, mycobacteria, Streptococcus pneumoniae, Haemophilus in \202 uenzae, varic ella-zoster). CLINICAL ASSESSMENT 69 Initial investigations \200 CXR appearance is very variable; may be normal or show consolidation, nodular in \201 ltra te, or diffuse shadowing. CXR is of limited diagnostic value, as appearances are non-speci \201 c and atypical presentations are common; the \200\230 \201 rst-choice \200\231 diag nosis based on CXR is correct in only a third of cases. CXR may, however, be helpful in mon itoring disease progression and response to treatment Blood and pleural \202 uid (if avai lable) sampling for microscopy and culture. Consider viral serology (e.g. CMV following tra nsplantation), urinary Legionella antigen Sputum examination is often of little diagnostic value in immunocom- promised patients, with the possible exceptions of invasive aspergillos is and tuberculosis. Send sputum for acid-fast stain and mycobacterial culture, fungal stai n, and culture. Induced sputum has a low yield for PCP in non-HIV patients The degree of hy poxia is often not appreciated; measure oxygen saturations and consider ABGs. Severe hypoxi a tends to be more commonly associated with infection due to bacteria, viruses, or Pneumocy stis than with mycobacteria or fungi. Is immediate antibiotic treatment required? Immediate empirical treatment with broad-spectr um antibiotics prior to further investigation should be considered, depending on the nature of immunological defect and local hospital policy. In general, neutropenic patients with f ever are at signi \201 cant risk of developing overwhelming sepsis, and should receive pro mpt antibiotic cover, irrespective of the CXR appearance and pres- ence or absence of respi ratory symptoms/signs. More invasive diagnostic procedures can then be reserved for patient s who deteriorate or fail to improve within a period of observation (e.g. 2 \200\2233 days) . In non-neutropenic patients, depending on the clinical circumstances, it is often possibl e to withhold treatment until de \201 nitive investigations have taken place. CHAPTER 12 Pulmonary disease (non-HIV) 70 Further investigations More invasive diagnostic techniques are usually required for a de \201 nitive diagnosis. CT chest \200 Speci \201 c indications not yet de \201 ned. Probably not needed in typical cases of bac terial pneumonia or PCP Useful in identifying the location and extent of pulmonary disease, and aiding invasive sampling procedures Often detects pulmonary disease in the presence of a normal CXR \200\224 consider if respiratory symptoms or unexplained fever, but normal CX R May be diagnostic, e.g. pulmonary embolism (CTPA), lymphangitis carcinomatosis, invasive aspergillosis ( \200\230halo \200\231 and \200\230air crescent \200\231 signs). Bronchoscopy with bronchoalveolar lavage \200 First-line investigation; consider early in management. Diagnostic in about 60% of patients overall; up to 70% of patients with infection. Results in change to treatment in around 50 % of cases overall. Complications are rare Useful in the diagnosis of bacterial pneumonia, PCP (sensitivity 80 \200\22390%), cytomegalovirus (sensitivity 85 \200\22390%), aspergillos is (sensitivity 50%), tuberculosis, malignant disease, diffuse alveolar hemorrhage, and alv eolar proteinosis BAL \202 uid analysis \200\224routine microscopy and culture for bacter ia; additional stains and culture for fungi, mycobacteria, Nocardia; silver or immuno \202 uorescence stain for Pneumocystis; cytology, including \202 ow cytometry, for malignant cells; viral serology; haemosiderin-laden macrophages if alveolar hemorrhage suspected Cons ider additional tests on BAL \202 uid, such as Cryptococcus antigen detection or CMV PCR. Aspergillus antigen detection or PCR and Toxoplasma gondii PCR are less well validated Tra nsbronchial biopsy has a slightly higher sensitivity than BAL for the diagnosis of infectio n, but carries a risk of bleeding and pneumothorax, which can be serious complications in t his patient group; it is not usually performed at initial bronchoscopy, although may be con sidered, e.g. if lymphangitis is suspected. Lung biopsy Consider as a second-line investigation if BAL is non- diagnostic. Options incl ude: \200 Repeat bronchoscopy with transbronchial lung biopsy is useful in the diagnosis of malignanc y, mycobacteria, fungi, organizing pneumonia, and drug-induced lung disease VATS or open lu ng biopsy has a greater diagnostic yield than TBB, although it is unclear if this can be di rectly translated into an improved survival. Results in change to treatment in <50% of pati ents and complications may be serious Percutaneous image-guided \201 ne-needle aspiration or biopsy for investigation of peripheral nodules. This page intentionally left blank CHAPTER 12 Pulmonary disease (non-HIV) 72 Causes Causes of pulmonary disease in the immunocompromised can be broadly divided into inf ectious and non-infectious; multiple disease processes are common. The nature of immunosupp ression may provide clues to the cause(s) of pulmonary disease \200\224solid organ (kidney and liver) transplants are further discussed on p 74, lung transplantation on p 317, HSCT o n p 75, and HIV on pp 79-83. Infectious causes (>75% of cases) Infection is the commonest c ause of respiratory disease in the immunocompromised. The nature of immuno- logical defect may provide clues to the likely infectious agent: \200 Neutropenia or impaired neutrophil function (e.g. secondary to leukemia or cytotoxic treatm ent) Bacteria (Pseudomonas aeruginosa, S. aureus, S. pneumoniae, E. coli, Klebsiella, H. in \202 uenzae, Nocardia), fungi (Aspergillus, Candida, Mucormycosis) Impaired T-lymphocyte function (e.g. secondary to transplantation, cytotoxic treatment, high-dose steroids, lymph oma, AIDS) Fungi (PCP, Cryptococcus neoformans, Candida, Histoplasma, Coccidioides, Blastom yces), viruses (cytomegalovirus, herpes simplex, varicella- zoster), bacteria (mycobacteria , Listeria, Legionella, Nocardia), parasites (Toxoplasma gondii) Hypogammaglobulinaemia or impaired B-lymphocyte function (e.g. secondary to myeloma, acute and chronic lymphocytic le ukemia, lymphoma) Encapsulated bacteria (S. pneumoniae, H. in \202 uenzae). It should be noted, however, that considerable overlap exists between immune de \201 cienc ies, and the pattern of infection will be further modi \201 ed by prophylactic treatment, e.g. CMV and PCP prophylaxis. Non-infectious causes (<25% of cases) Often present with simi lar, if not identical, clinical and radiological features to infection, and signs such as f ever do not reliably differentiate between them. Causes include: \200 \200 Pulmonary oedema Particularly following renal or HSCT transplant ARDS e.g. secondary to sep sis, drugs (e.g. cytarabine, gemcitabine, OKT3 antilymphocyte antibodies, interleukin-2), m assive blood trans- fusion, transfusion-related acute lung injury, aspiration, \200\230eng raftment syndrome \200\231 (coinciding with neutrophil engraftment) following HSCT Drug-ind uced disease Causes include all-trans retinoic acid (ATRA), antithymocyte globulin, azathio prine, bleomycin, busulfan, carmustine, chlorambucil, cyclophosphamide, cytosine arabinosid e, hydroxyurea, liposomal amphotericin B, melphalan, mitomycin, methotrexate, sirolimus Res piratory involvement from the underlying disease e.g. lymphoma, leukaemic in \201 ltration , lymphangitis carcinomatosis, connective tissue disease, leucostasis with very high leucoc yte counts in leukemia Pulmonary embolism Often complicated by secondary infection; clinica l/radiological features may be confused with invasive aspergillosis; may be more common aft er kidney transplant Radiation-induced pulmonary disease Pneumonitis (dyspnoea; clear margi ns on CT; typically follows lung radiotherapy) or organizing pneumonia (cough; extends beyo nd radiation \201 eld on CT; typically follows breast radiotherapy) CAUSES 73 Diffuse alveolar hemorrhage not uncommon complication of leu- kaemia, and allogeneic or aut ologous HSCT; similar clinical presenta- tion to that of pneumonia; haemoptysis is rare; mu ltilobar CXR/CT in \201 ltrates; proposed diagnostic criteria include exclusion of infecti on, progressively bloodier returns from BAL of three different subseg- mental bronchi (alth ough limited sensitivity and speci \201 city), and \211 20% of alveolar macrophages haemo siderin- \201 lled (although may require several days to appear); reported mortality range s 30 \200\223100% \200\230Idiopathic pneumonia syndrome \200\231 following allogeneic or a utologous HSCT; breathlessness with hypoxia and multilobar CXR/CT in \201 ltrates; infecti on excluded with BAL and ideally a second later investigation (e.g. repeat BAL or lung biop sy); diffuse alveolar damage or interstitial pneumonitis on biopsy; mortality >70% Engraftm ent syndrome comprises fever, ARDS, and erythematosus rash during marrow recovery post-HSCT Chronic air \202 ow obstruction (bronchiolitis obliterans) following allo- geneic HSCT (f rom non-identical sibling or unrelated individual; occurs only extremely rarely following a utologous procedure); typically associ- ated with chronic graft-versus-host disease (GVHD); gradual onset dry cough, dyspnoea, wheeze, obstructive spirometry; CXR often normal; air-t rapping and bronchial dilatation on HRCT; TBB low sensitivity; may be complicated by Asperg illus infection; variable course Post-transplant lymphoproliferative disease most common fo llowing lung transplant (p 317); may also follow other solid organ or allogeneic HSC transp lant Pulmonary alveolar proteinosis (p 630) Pulmonary veno-occlusive disease Pulmonary meta static calci \201 cation may complicate chronic renal failure and rarely progress after tr ansplantation; usually asymptomatic, rarely causes restrictive ventilatory defect; CXR show s single or multiple nodules or patches of consolidation, may not appear calci \201 ed; CT typically diagnostic, although biopsy occasionally needed Right hemidiaphragm dysfunction is common after liver transplant, and usually not relevant clinically. \200 \200 Multiple disease processes About 30% of patients have two or more disease processes account ing for their respiratory involvement. Secondary infection with a different infectious agen t (commonly Aspergillus or Gram-negative bacteria such as Pseudomonas) may complicate eithe r a primary respiratory infection or a non-infectious process such as pulmo- nary embolism. Secondary infection is associated with a poor prognosis; consider particularly in patients who deteriorate after an initial response to treatment, and in patients who are neutropeni c. Pleural effusion Differential diagnosis in non-HIV immunocompro- mised patients includes cardiac failure and \202 uid overload, pulmonary embolism, drug-related, parapneumonic ( bacterial including Nocardia, fungal, e.g. PCP), or related to underlying disease (e.g. leu kaemic in \201 ltrates, lymphoma, chylothorax, myeloma). Pleural effusions are common afte r liver transplant: usually right-sided or bilateral transudates and resolve by third week; may require drainage if symptomatic. CHAPTER 12 Pulmonary disease (non-HIV) 74 Differential diagnosis of pulmonary complications based on time course after transplantatio n Solid organ transplantation First month post-transplant (recent surgery ITU) \200 Nosocomial bacterial infection (Gram-negative, S. aureus \200\224including MRSA, Legionella ) ARDS Pulmonary oedema Drug-induced Pulmonary embolism Pleural effusion (especially after liver transplant) Right hemidiaphragm dysfunction (after liver transplant). \200 \200 \200 \200 \200 Months 1 \200\2236 (maximal immunosuppression) \200 Opportunistic infection (CMV, PCP, Nocardia, Aspergillus, Scedosporium apiospermum) Drug-in duced Post-transplant lymphoproliferative disease. \200 Months >6 (reduction in immunosuppression, unless rejection) \200 Common community-acquired pathogens (Haemophilus in \202 uenzae, Streptococcus pneumoniae, Legionella, tuberculosis, non-tuberculous mycobacteria, PCP, endemic mycoses e.g. Histopla sma, viruses e.g. in \202 u- enza, para-in \202 uenza, adenovirus, RSV) Opportunistic pat hogens (see above) Post-transplant lymphoproliferative disease Pulmonary metastatic calci \201 cation. \200 \200 DIFFERENTIAL DIAGNOSIS OF PULMONARY COMPLICATIONS 75 Haematopoietic stem cell transplantation (HSCT) First month post-transplant (prolonged neut ropenia pre-engraftment) \200 Infection (bacteria, e.g. Pseudomonas aeruginosa, Escherich ia coli, Klebsiella pneumoniae, Haemophilus in \202 uenzae, Staphylococcus aureus, Legione lla species; fungi, e.g. Aspergillus; viruses e.g. herpes simplex, adenovirus) Pulmonary oe dema ARDS Transfusion-related acute lung injury Drug-induced Diffuse alveolar hemorrhage Id iopathic pneumonia syndrome. \200 \200 \200 \200 \200 Months 1-3 (impaired cellular immunity post-engraftment, related in part to immunosuppressi ve drugs and GVHD) \200 Opportunistic infection (Gram-negative bacteria, Nocardia, CMV, herpes simplex, PCP) Drug-i nduced Diffuse alveolar hemorrhage Idiopathic pneumonia syndrome Engraftment syndrome Post- transplant lymphoproliferative disease Pulmonary veno-occlusive disease. \200 \200 \200 \200 \200 Months >3 (poor lymphocyte function, particularly following allogeneic HSCT) \200 Infection (Gram-positive bacteria, CMV, herpes, varicella-zoster, tuberculosis, non-tubercu lous mycobacteria, PCP, Aspergillus, endemic mycoses, e.g. Histoplasma) Chronic air \202 o w obstruction (bronchiolitis obliterans, associated with GVHD) Post-transplant lymphoprolif erative disease Pulmonary veno-occlusive disease. \200 CHAPTER 12 Pulmonary disease (non-HIV) 76 Treatment Antimicrobials Depending on the clinical circumstances, antimicrobials may need t o be started prior to de \201 nitive investigations (see p 69), although blood cultures sh ould always precede antibiotic treatment. Choice of anti- microbial depends on the underlyi ng condition and local hospital policy. \200 In general, most neutropenic patients are treated with broad-spectrum antibiotics providing both Gram-positive and Gram-negative cover, e.g. piperacillin (4.5 g IV qds); antifungals are considered if slow response to treatment or subsequent deterioration. Consider vancomyc in if MRSA is a possibility Treatment for CMV and PCP is associated with signi \201 cant s ide-effects, and ideally should be based on a de \201 nitive diagnosis. In unwell patients who are strongly suspected to have PCP, treatment (p 478) can be started immediately, as B AL Pneumocystis jiroveci stains remain positive for up to 2 weeks Antituberculous treatment should only rarely be administered in the absence of a microbiological diagnosis.