Pulmonary embolus, pulmonary hypertension, and vasculitides

Essential respiratory medicine. Shanthi Paramothayan

Chapter 11. Pulmonary embolus, pulmonary hypertension, and vasculitides

Learning objectives

■ To understand the risk factors for thromboembolic disease and how to calculate the probability score

■ To understand the clinical presentation of an acute pulmonary embolus

■ To understand the investigations for diagnosing acute pulmonary embolus

■ To understand the management of acute pulmonary embolus

■ To recognise the clinical presentation, investigations and management of chronic pulmonary emboli

■ To understand the aetiology and clinical presentation of pulmonary hypertension

■ To appreciate the investigations and diagnosis of pulmonary hypertension

■ To understand the management of pulmonary hypertension

■ To appreciate the differential diagnoses of pulmonary haemorrhagic syndromes

■ To appreciate the clinical presentation, diagnosis and management of granulomatosis with polyangiitis

■ To recognise the clinical presentation, diagnosis and management of eosinophilic granulomatosis with polyangiitis

■ To understand the clinical presentation, diagnosis and management of anti-glomerular basement membrane antibody disease

■ To understand the clinical presentation, diagnosis and management of hereditary haemorrhagic telangiectasia

Abbreviations

ABG arterial blood gas

ABPA allergic bronchopulmonary aspergillosij

ANCA anti-neutrophil cytoplasmic antibodies

APTT activated partial thromboplastin time

AVM arterio-venous malformation

BMPR2 bone morphogenetic protein receptor 2

CO carbon monoxide

COPD chronic obstructive pulmonary disease

CPFE combined pulmonary fibrosis and emphysema

CTEPH chronic thromboembolic pulmonary hypertension

CTPA computed tomography pulmonary angiogram

CUS compressive lower extremity ultrasounc

CXR chest X-ray

DVT deep vein thrombosis

ECG electrocardiogram

ECHO echocardiogram

eGFR estimated glomerular filtration rate

EGPA eosinophilic granulomatosis with polyangiitis

ELISA enzyme linked immunosorbent assay

GPA granulomatosis with polyangiitis

Hb haemoglobin

HDU high dependency unit

HHT hereditary haemorrhagic telangiectasia

HIT heparin induced thrombocytopaenia

HIV human immunodeficiency virus

HRCT high-resolution computed tomography

ICU intensive care unit

ILD interstitial lung disease

INR International Normalised Ratio

IVC inferior vena cava

JVP jugular venous pressure

IVUFH intravenous unfractionated heparin

KCO transfer coefficient

kPA kilopascals

LMWH low molecular weight heparin

LTOT long term oxygen therapy

MPA microscopic polyangiitis

MPO myeloperoxidase

MRPA magnetic resonance pulmonary angiogram

NICE National Institute for Health and Care Excellence

NYHA New York Heart Association

OSA obstructive sleep apnoea

PAH pulmonary arterial hypertension

PAP pulmonary artery pressure

PDGF platelet derived growth factor

PE pulmonary embolus

PESI Pulmonary Embolism Severity Index

PGI₂ prostaglandin

PHT pulmonary hypertension

PPH primary pulmonary hypertension

PPV positive predictive value

PR3 proteinase 3

PVOD pulmonary veno-occlusive disease

SCUFH subcutaneous unfractionated heparin

SLE systemic lupus erythematosus

SSRI selective serotonin reuptake inhibitors

TED thromboembolic disease

TGF transforming growth factor

TLCO carbon monoxide transfer factor (diffusing capacity)

TTE transthoracic echocardiogram

UFH unfractionated heparin

UK United Kingdom

VEGF vascular endothelial growth factor

VQ ventilation perfusion

VTE venous thromboembolism

WHO World Health Organisation

Introduction

Diseases of the pulmonary vasculature can present with symptoms of breathlessness, chest pain and haemoptysis. In some cases, these disorders can be life-threatening. Some conditions, such as pulmonary emboli, are relatively common. Pulmonary vasculitides, which can present with pulmonary haemorrhage and life-threatening haemoptysis, can involve other organs and are much rarer. Pulmonary embolism, pulmonary hypertension and some of the commoner pulmonary vasculitic conditions are discussed in this chapter.

Pulmonary embolism

A pulmonary embolus (PE) is caused by the obstruction of one, or both, of the pulmonary arteries or one of its branches by thrombus. Pulmonary arteries can also be blocked by air, fat or tumour cells, but these will not be discussed in this chapter.

Thromboembolic disease is a term used for the development of deep vein thrombosis (DVT) in the deep veins of the legs and pelvis which then break off and travel to the lungs, causing obstruction of the pulmonary vasculature. DVT and PE develop when there is venous stasis, endothelial damage, and hypercoagulability, described as Virchow’s Triad (Figure 11.1). Table 11.1 lists the risk factors for developing DVT and PE.

It is estimated that there are 120 cases of PE/100 000 population with the incidence increasing to 500/100 000 in those aged over 75 years. PE is estimated to be responsible for 0.5% of all deaths in Europe, the majority of which occur in hospitals. It is estimated that 1% of patients admitted to hospital develop an acute pulmonary embolus (PE), which is responsible for 5% of all deaths in hospital. There is a higher incidence of PE in African Americans and the incidence is less common in Asians.

All patients admitted to hospital should have a careful assessment and documentation of their risk of developing thromboembolic disease. Patients who have had surgery and who are immobile are at a particularly high risk of developing venous thromboembolism (VTE) because of venous stasis.

Table 11.1 Risk factors for developing thromboembolic disease.

Hypercoagulability	Stasis	Endothelial damage
Malignancy	Immobility	Previous DVT
Thrombophilia	Obesity	Thrombophlebitis
Pregnancy	Pregnancy	Lower limb trauma
Oral contraceptive pill	Long haul flight
Sepsis	Low cardiac output

Pregnant women also have an increased risk because of their hypercoagulable state and the occlusion of the pelvic veins caused by the enlarging uterus. Acute pulmonary embolus is the leading cause of maternal deaths in the UK. Patients with inherited thrombotic disorders, such as Factor V Leiden and prothrombin gene mutations, who may have a family history of thromboembolic disease, are also at an increased risk of developing PE, as are those with malignancy.

Prophylaxis with a low dose of low molecular weight heparin (LMWH) is recommended for those who are at risk, unless they have a risk of bleeding. Most patients who are going to have elective surgery and those who are immobile should be prescribed LMWH. It should be continued for a period after discharge from hospital. Patients who are ambulant with no specific risk factors may not require LMWH prophylaxis. Thromboembolic disease (TED) stockings are also used to prevent the development of DVT. If LMWH is contraindicated, for example because of an increased risk of bleeding or renal failure, then intravenous unfractionated heparin (UFH) infusion, which has a shorter half-life and can be reversed more quickly, can be considered. Patients who have had a stroke should be offered graded elastic compression stockings (TED stockings) and mechanical calf pumps. All patients should be encouraged to mobilise as early as possible.

Thromboprophylaxis is not required for most patients who are undertaking long journeys, including long-haul flights. Travellers should be reminded to keep hydrated, mobilise frequently, and do calf exercises to prevent venous stasis. High risk patients may require LMWH prior to a flight that is more than 12 hours long.

Acute pulmonary embolus

An acute PE is a common, and sometimes fatal, form of venous thromboembolism which should be considered in anyone presenting with dyspnoea, pleuritic chest pain, haemoptysis, hypotension, or cardiac arrest. The severity of symptoms will depend on how much the pulmonary circulation is occluded and where the emboli are. The clinical presentation can be highly variable and often non-specific.

Symptoms of a PE can occur acutely (within seconds or minutes), sub-acutely (over days or weeks), or occur slowly over many months, resulting in chronic thromboembolic pulmonary hypertension (CTEPH), which is discussed later in this chapter.

Prompt diagnosis and treatment of PE will reduce morbidity and mortality. A comprehensive history should include ascertaining the risk factors for developing thromboembolic disease and the calculation of a probability score.

Box 11.1 lists the commonest symptoms of a pulmonary embolus as determined in the Prospective Investigation of Pulmonary Embolism Diagnosis 11 (PIOPED 11) Study.

Patients usually develop sudden onset of breathlessness within minutes, especially if the thrombus blocks the main or lobar pulmonary vessels. However, patients may experience very mild symptoms or be asymptomatic, even with a large PE, and present after a delay of days or weeks. In a systematic review of studies, one-third of patients with DVT were found to have an asymptomatic PE.

Pleuritic chest pain is more likely to develop with smaller, more peripheral emboli, which result in inflammation of the visceral pleural membrane. This can lead to pulmonary infarction in 10% of cases, resulting in haemoptysis.

Box 11.1 Common symptoms of pulmonary embolus.

• Dyspnoea at rest or exertion (73%)

• Pleuritic chest pain (44%)

• Calf or thigh pain and swelling (44%)

• Dry cough (37%)

• Orthopnoea (28%)

• Wheezing (21%)

• Haemoptysis (13%)

_____

Box 11.2 Common clinical signs on examination in PE.

• Tachypnoea (54%)

• Calf/thigh swelling (47%)

• Tachycardia (24%)

• Crackles (18%)

• Loud P₂ (15%)

• Raised JVP (14%)

• Cardiovascular collapse (8%)

• Fever (3%)

_____

The differential diagnoses for anyone presenting with pleuritic chest pain and dyspnoea includes a variety of common respiratory conditions, such as acute asthma, pneumothorax, exacerbation of COPD, community acquired pneumonia, and heart failure.

The clinical signs of pulmonary embolus are relatively non-specific and include tachypnoea and a pleural rub if the patient presents late and has developed pulmonary infarction. Oxygen saturation measurement at rest may appear normal if the embolus is small, but a desaturation of more than 4% on exertion should alert the clinician to the possibility of a PE. PE should be suspected when there is hypotension and the JVP is elevated. If pulmonary embolus is suspected, then the lower limbs should be examined for evidence of a DVT which presents with leg swelling and pain on palpation. Box 11.2 lists the frequency of the common presenting signs on clinical examination.

A large saddle embolus, which lodges at the bifurcation of the main pulmonary artery and extends into the right and left main pulmonary arteries, occurs in 3—6% of cases and carries a mortality of 5%. These emboli can move distally and lodge in the segmental or sub-segmental branches.

Diagnosis of pulmonary embolus

It is recommended by NICE that a pre-test clinical probability score should be calculated in all patients with a suspected PE. In combination with simple investigations, this score can be used to decide whether further investigations are required. This is important as this avoids unnecessary investigations, such as a computed tomography pulmonary angiogram (CTPA), which exposes the patient to a high dose of radiation. However, it is important that a patient with risk factors for PE has appropriate investigations so that a PE is not missed.

Table 11.2 Modified Wells score.

Clinical feature	Points
Clinical symptoms of DVT	3
Other diagnosis less likely than PE	3
Heart rate > 100 bpm	1.5
Immobilisation or surgery within last 4 weeks	1.5
Previous DVT or PE	1.5
Haemoptysis	1
Malignancy	1
Score 2 or less: Low risk of PE. Score 2-4: Intermediate risk of PE. Score > 6: High risk of PE.

The NICE guidelines recommend the use of a two-level modified Wells score (Table 11.2) to assess the probability of an individual patient having a PE. A score greater than 4 indicates that a PE is likely and a score less than 4 suggests that a PE is unlikely. The Geneva score is an alternative score that is sometimes used.

Investigations in the diagnosis of pulmonary embolus

Most of the routine investigations that a patient will have when presenting to hospital are nonspecific and therefore not useful on their own in making or excluding a diagnosis of PE.

The ECG is often normal. The commonest ECG abnormality is sinus tachycardia. Other ECG changes, which occur in 70% of patients with a PE, include right heart strain, right axis deviation, depression of the ST segment, and T wave inversion in leads V1—V3. The S1Q3T3 pattern occurs in less than 10% of patients (Figure 11.2). Patients who develop bradycardia, atrial arrhythmias, new right bundle branch block, inferior Q-waves, and anterior ST-segment changes have a worse prognosis.

The chest X-ray (CXR) is normal in approximately 20%, and is an essential investigation to exclude pneumothorax, consolidation, and cardiac failure. A small pleural effusion is found in 47% of patients with a PE; this is often blood-stained if aspirated. Other radiological changes include atelectasis, pruning of the pulmonary vasculature with distal hypoperfusion, and a wedge-shaped opacity in the lung periphery (Figure 11.3).

Arterial blood gas (ABG) analysis is not a sensitive or specific test in the diagnosis of PE, but 74% of patients will be hypoxic. Approximately 41%

Figure 11.2 ECG changes seen in pulmonary embolus.

Figure 11.3 CXR showing right lower lobe infarction after a pulmonary embolism.

will have hypocapnia and a respiratory alkalosis. PE should be considered in anyone who has a normal CXR and unexplained hypoxaemia. Ventilation perfusion mismatch will result in widening of the Alveolar-arterial (A-a)gradient in the majority. The calculation of the A-a gradient is described in Chapter 13. Although not helpful on its own to make a diagnosis, the ABG at presentation may be of prognostic value. As patients with an initial oxygen saturation of less than 95% have an increased risk of respiratory failure and death, it is recommended that such patients are admitted to hospital for careful monitoring while undergoing investigations and treatment.

D-dimer is a breakdown product of cross- linked fibrin and levels will be elevated in patients with thromboembolism. Sensitive D-dimer testing using ELISA (enzyme-linked immunosorbent assay) is recommended. Although it is a sensitive test, with a greater increase in those with larger PEs, it lacks specificity. D-dimer levels will be elevated in those with any acute illness and in pregnant women. D-dimer levels will be falsely positive in patients with chronic renal failure with an estimated glomerular filtration rate (eGFR) <60 ml min^-1/1.73 m². The D-dimer level also increases gradually in patients over the age of 50 years. Age-adjusted D-dimer values may increase the specificity of the test, but this is not routinely done in the UK.

The D-dimer level is only useful in excluding a PE and should not be used to make a diagnosis of PE. According to the NICE guidelines, the D-dimer should be used in conjunction with the modified Wells score to determine the need for further investigations. If the modified Wells score is greater than or equal to 4, then the patient should go on to have further investigations to confirm the diagnosis of PE, regardless of the D-dimer level. In those with a high clinical suspicion of PE and a normal D-dimer level, the prevalence of PE is 20-28%.

If the probability of PE is considered unlikely (modified Wells score of less than 4), then a D- dimer level should be obtained. If this is negative, then no further testing is required. In those in whom the D-dimer level is elevated, a CTPA is required.

Although not sensitive or specific, serum Troponin I and T levels may indicate right ventricular dysfunction. Raised levels may be elevated in 30-50% of patients with a large PE and may be of prognostic value. The levels are rarely as high as would be after a myocardial infarction and return to normal within 2 days.

Imaging to confirm a diagnosis of PE

Computed tomography pulmonary angiogram (CTPA)

CTPA with intravenous contrast is a rapid test that is available in all hospitals in the UK. CTPA is the imaging of choice in a non-pregnant patient with normal renal function who is haemodynamically stable and not allergic to contrast. CTPA may not be the optimal investigation in the morbidly obese patient and in women under the age of 40 because of the high dose of radiation to the breasts, which may increase the risk of breast cancer.

An algorithmic approach which combines CTPA with clinical assessment and D-dimer levels increases the sensitivity and specificity of the test. CTPA has a sensitivity of over 90% for the diagnosis of PE, which increases to 96% when combined with a clinical probability assessment. The specificity of CTPA is 95%. When the modified Wells score is <2, the positive predictive value (PPV) of CTPA is 58%. If the Wells score is 2-6, then the PPV is 92% and for a Wells score >6, the PPV rises to 96%.

A PE will appear as a filling defect in a branch of the pulmonary artery which is otherwise filled with contrast (Figure 11.4). CTPA is most accurate for the detection of a large PE blocking the main, lobar, and segmental pulmonary arteries. It is less accurate for detecting smaller, peripheral, sub-segmental PEs. The modern multi-detector scanners can detect smaller, more peripheral emboli. The CTPA also has the advantage of finding other abnormalities which may be responsible for the clinical symptoms and signs.

Figure 11.4 CTPA showing bilateral filling defects seen with multiple pulmonary emboli.

A positive CTPA will confirm a diagnosis of PE and a negative CTPA means that a PE is unlikely. When the clinical suspicion is high but the CTPA is negative, 5% will have a PE. Therefore, patients with a high Wells score and a negative CTPA may require further investigations, which may include a VQ scan or a contrast-enhanced pulmonary angiogram.

Ventilation perfusion scan (VQ scan)

A VQ scan should be considered in any patient in whom a CTPA is contraindicated as discussed above. It should also be considered in women under the age of 40. A normal CXR is necessary when interpreting the VQ images and is, therefore, not a suitable investigation in a patient with chronic lung disease. A VQ scan may occasionally be indicated if the clinical suspicion of a PE is high but the CTPA is negative. A VQ scan is a nuclear medicine scan that is not available in all centres and not available out of hours because radioactive isotopes are required.

The PIOPED 11 study is the largest study to date which looked at the sensitivity and specificity of VQ scanning. A VQ scan has a moderately high sensitivity but a poor specificity, with a high number of false positive test results. As with CTPA, diagnostic accuracy was greater when the results of the VQ scan was combined with a clinical probability score.

A VQ scan is reported according to whether there are areas which have normal ventilation but abnormal perfusion (VQ mismatch). Patients with underlying lung disease, for example, COPD, will have matched ventilation and perfusion defects. A VQ scan can be reported as normal, low-probability of PE, intermediate probability of PE, or high-probability of PE.

A normal VQ scan means that a PE is unlikely, and no further investigations are required. A patient with a Wells score <2 and a normal or low-probability VQ scan will have <4% chance of having a PE. If this is combined with a normal D- dimer level, then the chance of a PE is <3%. A high probability VQ scan in a patient with a high clinical probability score means that there is a 96% chance of a PE (Figure 11.5). Patients with a low probability or inconclusive VQ scan will need further investigations (Figure 11.6).

Patients with a high clinical suspicion of PE in whom a CTPA is either negative or contra-indicated and in whom the VQ scan is inconclusive will require further imaging.

A contrast-enhanced pulmonary angiogram is historically the definitive test for diagnosing PE and has a good sensitivity and specificity. Although it is an invasive test and is associated with a small risk of harm, it is safe and well tolerated in haemodynamically stable patients with <2% mortality. Complications include catheter-related events, contrast-related complications, and cardiac complications. One advantage of this test is that if a clot is directly visualised, it can be lysed by embolectomy and/or thrombolysis if anticoagulation is contra-indicated.

A magnetic resonance pulmonary angiogram (MRPA) is less sensitive and specific and is rarely used. Proximal vein compressive lower-extremity ultrasound (CUS) can detect a DVT so can indirectly make a diagnosis of PE. It is not recommended in routine practice for diagnosing PE as only 9-12% of patients with PE are found to have a DVT by this method. However, in those in whom other investigations are contra-indicated, serial CUS done weekly for several weeks could be useful to detect DVT if the clinical suspicion is high. It is a valuable test in pregnant women as there is no exposure to radiation.

Figure 11.5 Ventilation perfusion scan showing perfusion defects in pulmonary emboli.

Figure 11.6 Ventilation perfusion scan showing VQ mismatch.

A transthoracic echocardiogram cannot make a diagnosis of PE, but in 30-40% of patients with a PE there will be changes consistent with right ventricular strain, which includes regional wall motion abnormalities that spare the right ventricular apex. In severe PE, there may be evidence of elevated right ventricular pressures, an increase in right ventricular size, tricuspid regurgitation, and pulmonary hypertension. In 4% of cases, a thrombus may be seen in the right ventricle, which confers a poor prognosis. The echo changes may be of prognostic value and resolution of changes can be used to monitor improvement with anticoagulation and, sometimes, to guide the length of anticoagulation. An echocardiogram can also diagnose other causes of hypotension and cardiovascular collapse, including aortic dissection and pericardial tamponade.

PE is a leading cause of mortality during pregnancy and in the 6 weeks post-partum, accounting for 20-30% of maternal deaths. It is difficult for the clinician to calculate the clinical probability of a pregnant woman having a PE as there are no validated scores in this group of patients. The imaging to use in a pregnant woman often causes much concern for the doctor and the patient. All pregnant women who present with possible PE should have a CXR (with lead protection for the foetus) which may suggest an alternative diagnosis. Both CTPA and VQ scan will expose the foetus to some radiation. CTPA exposes the mother’s breasts to a significant dose of radiation at a time when they are particularly metabolic, thus increasing the future risk of breast malignancy. It is recommended that a CUS of legs and pelvis is a useful initial investigation in a pregnant woman if PE is suspected. If this is normal but the presentation is suggestive of a PE, then a half-dose perfusion scan is recommended. CTPA is reserved for pregnant women who are clinically unwell and in whom other investigations are indeterminate.

Management of acute pulmonary embolus

Patients with suspected PE should receive oxygen and analgesia as required. Those with a high probability of PE (Wells score > 6) should receive LMWH while they are having investigations. Those with a moderate clinical probability (Wells score of 2-6) should be anticoagulated if the diagnosis is going to take more than 4 hours. It is recommended that all the diagnostic tests should be done within 4 hours. Patients with a low risk of PE should undergo investigations within 24 hours and do not require anticoagulation while waiting for the results.

Anticoagulation

Anticoagulation is the main treatment for PE. The risk of PE recurrence is 25% in patients with a high probability score and anticoagulation has been shown to reduce this. The main complication of anticoagulation is bleeding, and intracranial bleeding may be life-threatening. The risk of bleeding is estimated to be 1.6% in the first 3 months in those with no risk factors for bleeding and will be up to 3% in those with risk factors. Minor haemoptysis, epistaxis, and menstruation are not contraindications to anticoagulation. Anticoagulation has also been shown to reduce mortality, the benefits outweighing the risk of major bleeding.

The aim of anticoagulation is to reach a therapeutic level within 24 hours of treatment using either LMWH, subcutaneous fondaparinux, intravenous unfractionated heparin (IVUFH), or subcutaneous unfractionated heparin (SCUFH). A patient diagnosed with PE with a high risk of haemorrhage should be discussed with an expert prior to anticoagulation.

LMWH is recommended in haemodynamically stable patients with normal renal function. It is not indicated in patients who are morbidly obese as there is decreased absorption of medication given subcutaneously. Advantages of LMWH over IVUFH include lower mortality, fewer recurrent thromboembolic events, fewer major bleeding episodes, and a lower incidence of heparin induced thrombocytopaenia (HIT). LMWH has more predictable pharmacokinetics than UFH, requires twice daily administration of a fixed dose, and monitoring of anti-Xa levels is not required. The choice of which LMWH to use will be dictated by the cost and clinical experience. The dose is calculated according to the patient’s weight and given subcutaneously by injection.

LMWH is also recommended for the treatment of PE in a pregnant woman and more careful monitoring is recommended. Anticoagulation should be continued for 3 months after birth if pregnancy is the only risk factor for developing the PE. Those with other risk factors may need a longer period of anticoagulation. Warfarin is teratogenic so is contraindicated in pregnancy, particularly in the first trimester. Warfarin is, however, considered to be safe in breastfeeding mothers.

IVUFH is recommended in patients with massive PE and hypotension as they may require thrombolysis and the effects of the UFH can be reversed with protamine sulphate more rapidly than when patients receive LMWH or fondaparinux. IVUFH is also indicated in those in whom there is an increased risk of bleeding, those with renal failure (creatinine clearance less than 30 ml min^-1) and in the morbidly obese. Patients on UFH will require monitoring of their activated partial thromboplastin time (APTT).

Oral anticoagulation

Warfarin, a vitamin K antagonist, which blocks the production of the vitamin-K dependent clotting factors (11, V11, 1X and X), is the drug most commonly used for the long term treatment of PE. It is effective in preventing recurrent PEs and DVTs. Warfarin can be started as soon as the diagnosis of PE is confirmed while the patient is on the treatment dose of LMWH but should not be started without prior treatment with LMWH as there is evidence that this may increase the incidence of PE and/or DVT. It is recommended that LMWH treatment should continue for at least 5 days after starting treatment and until the International Normalised Ratio (INR) has been therapeutic (between 2 and 3) for at least 24 hours. This is because it takes at least 5 days for the intrinsic clotting pathway activity to be suppressed. It is recommended that the starting dose of warfarin should be 5 mg for 2 days and then the dose calculated according to the INR. The effects of warfarin can be reversed by giving vitamin K. Fresh frozen plasma can also be given if necessary.

Warfarin is a cheap drug but has a narrow therapeutic range and requires monitoring. Warfarin is a drug that has interactions with other commonly used drugs which are metabolised through the cytochrome P450 system. Doctors should be aware of these interactions. Certain food items, particularly those containing vitamin K, can also alter warfarin levels, so patients should be given information booklets with details of foods to avoid.

Increasingly, Factor Xa inhibitors, such as rivoroxaban, apixaban, and edoxaban are being used. Dabigatran, a direct thrombin inhibitor, is also being used in certain circumstances. These are fixed dose agents that do not require monitoring. However, the effects cannot be easily reversed. It is not within the scope of this book to discuss these newer anticoagulants in detail.

Patients with PE who are haemodynamically stable, not hypoxaemic, not in respiratory distress, who do not have significant co-morbidities, no increased risk of bleeding, and who do not live alone can be safely anticoagulated at home.

Duration of anticoagulation

The length of time that anticoagulation should be continued depends on the underlying cause of the PE. Rates of clot resolution with anticoagulant therapy are variable. It is estimated that there is resolution of the PE in 40% of patients within 1 week, in 50% within 2 weeks and in 73% within 4 weeks. Thrombi can also move during anticoagulation.

If the DVT and/or PE is due to an identifiable risk factor, such as immobility or surgery, the guidelines recommend 3 months of anticoagulation, so long as the INR is therapeutic during this period. The patient should be reviewed after this period to ensure that the symptoms have resolved and that there is no evidence of pulmonary hypertension.

Patients who have an ongoing risk of thromboembolism, such as an inherited clotting disorder, will require lifelong anticoagulation. Patients with an unprovoked PE, with no obvious risk factors, should have a thorough clinical assessment and appropriate investigations to exclude malignancy. They may require life-long anticoagulation as the risk of recurrence is 25% at 5 years without anticoagulation. The risk of bleeding is estimated to be 1.2% at 5 years. The risk of PE recurrence if anticoagulation is stopped, together with the risk of bleeding with continuing anticoagulation, should be discussed.

Patients with malignancy have an increased risk of PE. LMWH is recommended for patients with malignancy who develop PE. These patients also have an increased risk of bleeding, so the decision as to which anticoagulation to use, and for how long, must be made after weighing up the pros and cons for each patient.

Inferior vena cava filter

An IVC filter should be considered in anyone with a diagnosis of PE who has a significant risk of haemorrhage if commenced on anticoagulation. This includes those who are more than 65 years old, those with recent surgery, known haematological risk factors, liver failure, and malignancy. Patients who have extensive DVT and pelvic malignancy may also have recurrent episodes of PE as the clot breaks off and travels to the lungs. Retrievable filters are recommended, and the majority are placed infra-renally to prevent further emboli from reaching the lungs. This is usually a temporary solution and the filter will need to be removed once anticoagulation has been optimised.

Management of massive life-threatening pulmonary embolus

Approximately 8% of patients with a PE present with shock and collapse. Patients who have a systolic blood pressure of less than 90 mmHg may not be well enough for a CTPA to confirm the diagnosis but must rely on a bedside transthoracic echocardiogram which will show signs of right heart strain. Patients who present with a suspected massive pulmonary embolus with haemodynamic compromise, signs of right heart strain on transthoracic echocardiogram and or bilateral or saddle embolus on CTPA should be thrombolysed.

Patients should have immediate, but careful, intravenous fluid resuscitation, oxygen therapy to maintain the oxygen saturation between 94% and 98% and vasopressor support. If the intravenous fluid is given too aggressively, there is a risk of right ventricular failure. While waiting for confirmation of a PE, the patient should be commenced on IVUFH. Patients should receive 50 mg of alteplase as a bolus via a peripheral vein followed by intravenous heparin infusion. The activated partial thromboplastin time (APTT) should be maintained at between 1.5-2.5 times normal. Analgesia will be required for pain. Oral anticoagulation, usually with warfarin, should be started with a loading dose of 10 mg, with an aim to maintain the INR between 2 and 3.

Thrombolysis can increase the risk of cerebral and pulmonary haemorrhage. The decision to thrombolyse should be made by a senior respiratory physician after consultation with a radiologist and intensivists. Such patients should be managed in a high dependency unit (HDU) or intensive care unit (ICU).

If thrombolysis is contra-indicated, for example, in a pregnant patient, or it fails, then catheter-directed embolectomy or surgical embolectomy should be considered. These procedures are only available in tertiary centres and are associated with a high mortality.

Prognosis after acute PE

The overall mortality without treatment is 30% but reduces to 2-11% with anticoagulation. The risk of death is highest in the first week due to cardiogenic shock. The risk of recurrent PE is also greatest in the first 2 weeks. In the longer term, mortality is due to the underlying condition that caused the PE, such a malignancy.

The Pulmonary Embolism Severity Index (PESI) can be used to calculate the risk of death. Poor prognostic factors include age more than 65 years, co-morbid conditions, shock, right ventricular failure, hypoxaemia, thrombus in the right ventricle, elevated brain natriuretic peptide and N-terminal pro-brain natriuretic peptide, and elevated troponin I and T levels.

Recurrent pulmonary emboli

Patients with recurrent, acute PE may require life-long anticoagulation. Compliance with treatment should be checked, ensuring that the INR is therapeutic. Some patients, especially those with malignancy or pelvic DVTs, may have recurrent pulmonary emboli despite anticoagulation. In some patients it can be difficult to maintain the INR in the therapeutic range. In these patients, and those in whom anticoagulation is contra-indicated, an inferior vena cava filter should be considered. If a patient with a known diagnosis of PE, who is already being anticoagulated, presents with symptoms and signs of a PE, the same diagnostic approach should be taken. Images should be carefully reviewed by the radiologist as interpretation may be difficult.

Chronic pulmonary emboli

Patients with chronic pulmonary emboli will present with progressively worsening breathlessness and clinical features of pulmonary hypertension, which includes raised JVP, peripheral oedema, and parasternal heave. The ECG may show right ventricular hypertrophy and right axis deviation. The CXR will show prominent pulmonary arteries. A VQ scan will demonstrate unmatched defects. These patients are at risk of developing chronic thromboembolic pulmonary hypertension (CTEPH), which will be discussed in the next section.

Pulmonary hypertension

Pulmonary vascular tone is dependent on the balance of vasoconstrictors and vasodilators. Oxygen is a potent vasodilator, therefore hypoxia results in vasoconstriction.

Figure 11.7 Regulation of pulmonary vascular tone.

Table 11.3 WHO classification of pulmonary hypertension.

Type Aetiology Management
Group 1: Pulmonary arterial hypertension	Familial Appetite suppressants	Prostacyclin Endothelin receptor antagonist Phosphodiesterase-5 inhibitor
Group 2: Left heart disease: elevated left atrial pressure and pulmonary venous hypertension	Congenital cardiomyopathies Valvular heart disease Outflow tract obstruction Left ventricular systolic dysfunction Left ventricular diastolic dysfunction	Management of underlying condition Anticoagulation LTOT
Group 3: Severe lung disease	All causes of hypoxaemia, including COPD, ILD, sleep disordered breathing, alveolar hypotension	Management of underlying condition Anticoagulation LTOT
Group 4: Thromboembolic disease (CTEPH)	Develops secondary to chronic occlusion of proximal or distal pulmonary vessels	Thromboendarterectomy
Group 5: Multifactorial	Sickle cell disease p-thalassaemia Spherocytosis Myeloproliferative disorders Sarcoidosis Glycogen storage disease Chronic kidney disease	Management of underlying condition Anticoagulation LTOT

Pulmonary hypertension presents with insidious onset of breathlessness, fatigue, and pre-syncope (Figure 11.7). When severe, patients can also experience atypical chest pains, peripheral oedema, palpitations, and syncope. Pulmonary hypertension can be due to a variety of different aetiologies as described in the WHO classification in Table 11.3. The NYHA Functional Classification (Box 11.3) is used to describe the severity of the dyspnoea.

Pulmonary hypertension can affect patients of all ages and ethnicities but occurs more commonly in African-Americans. The prevalence of pulmonary hypertension is estimated to be around 5-7/100000 of population. Pulmonary hypertension has a poor prognosis if not diagnosed and treated promptly.

Normal pressure in the pulmonary artery system is 20/8 mmHg. The mean pulmonary artery pressure is 12-15 mmHg. Pulmonary hypertension is defined as a mean pulmonary artery pressure (PAP) of greater than 3.3 kPa (25 mmHg) at rest or greater than 4.0 kPa (30 mmHg) on exercise. Pulmonary hypertension can occur due to pulmonary arterial hypertension alone or occur due to pulmonary venous hypertension.

Box 11.3 NYHA functional classification.

Class	Functional capacity	Objective assessment
I	No symptoms with normal physical activity	No objective evidence of cardiovascular disease
II	Minimal symptoms on physical exertion	Some evidence of cardiovascular disease
III	Moderately severe symptoms on physical exertion	Evidence of moderately severe cardiovascular disease
IV	Severe symptoms on exertion, symptoms present at rest	Evidence of severe cardiovascular disease

In patients presenting with symptoms suggestive of pulmonary hypertension a detailed history should include that of underlying lung disease (COPD, ILD, OSA), heart disease (including congenital heart disease), chronic thromboembolic disease, connective tissue disorders, and human immunodeficiency virus infection.

Clinical examination will reveal tachypnoea, tachycardia, and a loud second heart sound (P₂, the pulmonary component). In severe pulmonary hypertension there will be signs of right heart failure, which includes a parasternal heave, raised JVP, peripheral oedema, tricuspid regurgitation, and hepatomegaly. When pulmonary hypertension is due to an underlying condition, such as a connective tissue disorder, signs of that disease may be present.

Several investigations are required to make a diagnosis of pulmonary hypertension and to elucidate the cause of the pulmonary hypertension. The CXR in pulmonary hypertension will show large pulmonary arteries with pruning of the pulmonary vessels in the lung fields (Figure 11.8). The ECG will show tall p wave in leads 11, 1V, AVF (p pulmonale) with a tall R wave in V1, ST segment depression with T wave inversion in V1-V3 (Figure 11.9).

Figure 11.8 CXR showing right ventricular hypertrophy in a patient with severe pulmonary hypertension.

A transthoracic echocardiogram (TTE) is an essential investigation in a patient suspected of having pulmonary hypertension. It will show an enlarged right ventricle with right ventricular hypertrophy. The PA pressure can be estimated from the velocity of the tricuspid regurgitant jet. Right heart catheterisation is required to measure the mean pulmonary artery pressure, the pulmonary vascular resistance, to see if there are any thrombotic lesions and to assess the response to vasodilators. This is a specialist investigation that is conducted in a pulmonary hypertension centre.

An HRCT may be required to confirm the diagnosis of an ILD. A CTPA can confirm an acute pulmonary embolus and a VQ scan will be required to diagnose chronic pulmonary emboli.

Classification of pulmonary hypertension

Table 11.3 describes the WHO classification of Pulmonary Hypertension.

Group 1: Pulmonary Arterial Hypertension

Pulmonary hypertension due to pulmonary arterial hypertension (PAH) can occur due to a variety of different aetiologies that affect the small, muscular pulmonary arterioles. Box 11.4 lists these causes. This group was previously called Primary

Figure 11.9 ECG changes seen in pulmonary hypertension.

Box 11.4 Aetiology of pulmonary arterial hypertension.

• Idiopathic (sporadic)

• Familial (hereditary)

• Drugs and toxins

• Connective tissue diseases

• Human immunodeficiency virus infection

• Portal hypertension

• Congenital heart disease

• Schistosomiasis

____

Pulmonary Hypertension. The incidence of PAH is 1—2/million of population, with a prevalence of 8/ million of population. The peak incidence is in the 3rd and 4th decades of life with a female:male ratio of 2.4 : 1. There appears to be an increased incidence in Afro-Caribbean women. Patients with PAH should be managed in a centre with expertise in the management of this condition.

In genetically predisposed individuals, endothelial injury results in the release of a variety of cytokines, including endothelin and thromboxane, which are potent vasoconstrictors, and a reduction in the release of nitric oxide and prostaglandin I_2,which are potent vasodilators. These vasoconstrictors cause smooth muscle hyperplasia, medial hypertrophy, intimal thickening, and plexiform lesions of the muscular pulmonary arterioles (Figure 11.10, Figure 11.11). With time, there is vascular remodelling and increase in pulmonary vascular resistance. In addition, there is increased production of platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF) and transforming growth factor (TGF) which results in a hypercoagulable state with in situ thrombosis, which causes further damage to the vessels.

The idiopathic and familial types cannot be clinically separated. Of these, 90% of cases are sporadic and 10% of cases are familial. The majority (80%) of the familial group occur due to a mutation of the bone morphogenetic protein receptor 2 (BMPR2) which is inherited as an autosomal dominant trait with incomplete penetrance of 10—20%. The remaining 20% of the familial group is due to other genetic defects.

Some 25% of the sporadic cases also have a genetic mutation in BMPR2 gene. Most individuals with the mutation never acquire the disease but may transmit the mutation to their progeny. The estimated risk of acquiring the disease is 10%.

Some cases of pulmonary arterial hypertension have been associated with the use of appetite suppressant drugs, including aminorex, fenfluramines, dexfenfluramine, toxic rapeseed oil, diethylproprion, and benfluonex. Other drugs which have been implicated include L-tryptophan, amphetamines, methamphetamines, cocaine, and St. John’s Wort. When a pregnant woman takes selective serotonin reuptake inhibitors (SSRIs), this may result in persistent pulmonary hypertension of the newborn child. SSRIs can also worsen existing pulmonary arterial hypertension in adults.

Figure 11.10 Histology showing intimal proliferation in pulmonary hypertension.

Figure 11.11 Histology showing changes of pulmonary arterial hypertrophy.

Several connective tissue disorders, for example, rheumatoid arthritis and systemic lupus erythematosus, can result in pulmonary hypertension secondary to interstitial lung disease. This is more likely in females and more likely in those with Raynaud’s phenomenon. It is estimated that approximately 10—15% of patients with systemic sclerosis (scleroderma) develop pulmonary arterial hypertension caused by fibrous destruction of the alveolar capillaries, small arterioles, and arteries. The prognosis is very poor.

Approximately 0.5% of patients with HIV develop PAH through an unknown mechanism as do 1—6% of patients with portal hypertension secondary to chronic liver disease: this improves with liver transplantation. Congenital heart disease secondary to defects in the vascular system results in PAH due to an increase in pulmonary blood flow and pressure overload. Approximately 10% of children born with heart defects leading to left-to-right intracardiac shunts, for example, Eisenmenger’s syndrome, will develop PAH, even if the defect is repaired.

Schistosomiasis is the commonest cause of PAH worldwide, mainly affecting those with hepatosplenic involvement. The schistosome ova embolize to the lungs and cause a granulomatous reaction in the pulmonary arterioles.

A rare cause of PAH is pulmonary veno-occlusive disease (PVOD) resulting from the occlusion of the pulmonary veins and tortuous dilatation of the pulmonary capillaries.

Patients with Group 1 PAH have a worse prognosis than those in the other groups if no treatment is given, with a median survival of 3 years.

Group 2: Pulmonary hypertension secondary to left heart disease

In this group, pulmonary hypertension develops due to elevation of the left atrial pressure and pulmonary venous pressure. This can develop secondary to left ventricular systolic or diastolic dysfunction, valvular heart diseases (particularly severe mitral regurgitation), inflow or outflow tract obstruction, and congenital and restrictive cardiomyopathies. Rarer causes include left atrial myxoma, constrictive pericarditis, and morbid obesity which can cause pulmonary hypertension by causing severe diastolic dysfunction. It is important to measure the pulmonary capillary wedge pressure and the left ventricular end-diastolic pressure accurately.

Group 3: Pulmonary hypertension secondary to lung disease

Common causes of pulmonary hypertension in this group include COPD, ILD combined pulmonary fibrosis and emphysema (CPFE), obstructive sleep apnoea (OSA) and disorders of alveolar hypoventilation. Hypoxaemia is a powerful stimulus for pulmonary vasoconstriction, which can result in pulmonary hypertension.

Mild pulmonary hypertension is prevalent in patients with COPD and confers a worse outcome. Patients with severe pulmonary hypertension, with a mean pulmonary artery pressure (PAP) of more than 45 mmHg, have less than 10% 5-year survival. Patients with ILD can develop pulmonary hypertension secondary to hypoxaemia or develop PAH directly due to the involvement of the pulmonary vascular bed as discussed earlier. Patients with CPFE have a particularly high risk of developing pulmonary hypertension which carries a poor prognosis. It is estimated that up to 20% of patients with severe OSA develop PH.

Group 4: Pulmonary hypertension secondary to chronic thromboembolic disease (CTEPH)

Approximately 1—5% of patients who survive an acute pulmonary embolus will develop chronic thromboembolic pulmonary hypertension (CTEPH) due to occlusion of the proximal or distal pulmonary vasculature. It is hypothesised that abnormally elevated Factor VIII levels or the presence of antiphospholipid antibodies may predispose to the development of CTEPH.

Patients who develop CTEPH will present with progressively worsening dyspnoea, initially on exertion, but eventually at rest and develop symptoms and signs of right heart failure. A history of possible previous PE should be sought. As the differential diagnosis for this presentation is huge, the patient will usually undergo many investigations to exclude primary cardiac problems, obstructive airways disease, and restrictive airways disease. A ventilation perfusion (VQ) scan is the imaging modality of choice and will show several mismatched defects. Patients will require right heart catheterisation to measure the pulmonary artery pressure and to determine whether the thrombotic lesions can be surgically removed.

Group 5: Multifactorial pulmonary hypertension

Pulmonary hypertension can develop due to a variety of other aetiologies. Haematological causes include chronic haemolytic anaemia, sickle cell disease, β-thalassaemia, spherocytosis, and myeloproliferative diseases. Other causes include sarcoidosis and glycogen storage diseases.

Management of pulmonary hypertension

Medical management of pulmonary hypertension includes optimal management of the underlying condition that caused the pulmonary hypertension to limit progression. Specific management of right heart failure and pulmonary hypertension includes anticoagulation, diuretics, and long term oxygen therapy (LTOT).

Advanced therapy is recommended for patients with Group 1 PAH. These treatments are generally not recommended for those with other types of pulmonary hypertension. Patients must be assessed in a specialised unit and have a diagnostic right heart catheter and vasoreactivity testing to determine which medications are likely to be beneficial.

Calcium channel antagonists, which cause vasodilation, may be beneficial and will demonstrate vasodilatation during right heart catheterisation. Diltiazem is the most commonly used agent.

Prostacyclin (PGI₂), an endogenous substance derived from arachidonic acid and produced by vascular endothelial cells, is reduced in pulmonary hypertension. PGI₂ has a variety of effects, including vascular smooth muscle relaxation resulting in vasodilatation, inhibition of smooth muscle proliferation and inhibition of platelet activity. Prostacyclin has a very short half-life in vivo.

Prostacylin (epoprostenol) is most effective when given intravenously through an in-dwelling catheter. Epoprostenol improves cardiopulmonary haemodynamics by causing vasodilation, and reduces pulmonary vascular resistance, thereby improving breathlessness and exercise capacity. Epoprostenol also improves life expectancy. This treatment is reserved for patients who are symptomatic with a NYHA stage of III or IV. Catheter-related sepsis, haemodynamic instability, and thrombosis are common complications. Iloprost, the inhaled form of prostacyclin and treprostanil, given subcutaneously, also improve exercise capacity and cardiopulmonary haemodynamics, with fewer systemic side effects. The oral form (Beraprost) is less effective. The oral and inhaled prostacyclins are usually given to patients who are WHO functional class II or III.

Oral endothelin receptor antagonists, such as bosenten, ambrisentan, or macitentan, reduce vascular tone, intimal proliferation, pulmonary artery pressure and pulmonary vascular resistance. Selective oral phosphodiesterase-5 inhibitors, such as sildenafil and tadalafil, also decrease pulmonary artery pressure and can be taken orally. Oral guanylate cyclase inhibitor, riociguat, is also available.

Surgical treatment of pulmonary hypertension

Endarterectomy is indicated for patients with CTEPH. Atrial septostomy has also shown benefits in patients with severe pulmonary hypertension, especially as a bridge to lung transplantation. Heart or heart lung transplantation may be an option for young patients with severe pulmonary hypertension.

Pulmonary haemorrhagic syndromes

There are several pulmonary haemorrhagic syndromes which can present with life-threatening haemoptysis. Pulmonary vasculitic diseases usually occur as part of a generalised systemic vasculitis which may involve the kidneys and other organs. Systemic lupus erythematosus (SLE) can cause pulmonary haemorrhage while rheumatoid arthritis rarely causes pulmonary haemorrhage.

Most patients with a vasculitis will have antineutrophil cytoplasmic antibodies (ANCA), which are immunoglobulin G antibodies against antigens in the cytoplasm of the neutrophil granulocyte. Antibodies to the perinuclear antigens, including myeloperoxidase (MPO), results in a p-ANCA vasculitis, and antibodies to proteinase 3 (PR3) results in a c-ANCA vasculitis.

Severe pulmonary haemorrhage results in blood in the alveolar spaces which compromises oxygenation, resulting in hypoxaemia and respiratory failure. Diffusing capacity (TLCO) and transfer coefficient (KCO) will be increased and bloodstained fluid will be seen when bronchoalveolar lavage is performed.

Management of pulmonary haemorrhage secondary to a vasculitis is with immunosuppressive treatment and plasmapheresis to remove circulating antibodies. Supportive treatment includes oxygen, bronchodilators, reversal of any coagulopathy, blood transfusion, and mechanical ventilation in severe cases. Management of life threatening haemoptysis is discussed in Chapter 5.

Granulomatosis with polyangiitis (GPA)

Granulomatosis with polyangiitis, previously known as Wegener’s Granulomatosis, is a necrotising vasculitis affecting the upper airways, lungs, and kidneys. GPA presents with symptoms of rhinitis, sinusitis, blood-stained nasal discharge, epistaxis, and haemoptysis, which can result in extensive and life-threatening pulmonary haemorrhage.

The CXR and CT thorax often show cavitating nodules, the differential diagnosis for which includes malignancy, especially squamous cell carcinoma (see Chapter 9), infections such as Staphylococcus aureus, Mycobacterium tuberculosis and aspergillus fumigatus (see Chapter 8), and occupational lung diseases (see Chapter 15). A CT-PET will generally show increased FDG uptake and a CT-guided biopsy of the pulmonary nodule will show fibrinoid necrosis (Figure 11.12).

GPA also results in focal, necrotising glomerulonephritis, progressing rapidly to end-stage renal failure without treatment. Urea and electrolytes will be consistent with renal failure. Some 90% of patients with GPA will be c-ANCA positive and less than 10% will be p-ANCA positive. Renal biopsy will show fibrinoid necrosis.

Figure 11.12 CXR of a patient with granulomatosis with polyangiitis.

Management of GPA is with immediate immunosuppression with high doses of intravenous cyclophosphamide in combination with methyl- prednisolone. Most patients (70—90%) will achieve remission, and immunosuppression can be maintained with less toxic drugs, such as azathioprine, rituximab, or methotrexate. Relapses are common, especially in patients with involvement of the upper airways and lungs and those with Staphylococcus aureus in their nasal passages.

Other vasculitides

Polyarteritis nodosa is a vasculitis affecting medium and small arteries resulting in aneurysm formation, glomerulonephritis, and vasculitic lesions in various organs. Pulmonary involvement is unusual but may result in haemoptysis, pulmonary haemorrhage, fibrosis, and pleurisy. Microscopic polyangiitis (MPA) is a systemic, ANCA-positive vasculitis resembling GPA.

Anti-glomerular basement membrane antibody (Goodpasture’s) syndrome

Anti-glomerular basement membrane disease presents with rapidly progressive crescentic glomerulonephritis and alveolar haemorrhage due to circulating anti-basement membrane antibodies that bind to lung and renal tissue. Patients who are not diagnosed and treated promptly will progress to end-stage renal failure. There is clinical correlation between the initial plasma creatinine concentration and the severity of the renal disease.

Pulmonary involvement is more common in smokers, resulting in severe pulmonary haemorrhage and life-threatening haemoptysis. The CXR typically shows parenchymal infiltrates secondary to alveolar haemorrhage. Patients may become anaemic and require a blood transfusion. Type 1 respiratory failure can develop rapidly. A lung function test will show increased diffusing capacity (TLCO) because of the binding of inhaled CO to haemoglobin in the alveoli, and the transfer coefficient (KCO) will be increased. Bronchoalveolar lavage will reveal blood-stained fluid.

Management is with plasmapheresis to remove the circulating anti-basement membrane antibodies and complement. Immunosuppression with high dose methylprednisolone, followed by 1 mg kg^-1 of oral prednisolone and oral cyclophosphamide will reduce the production of new antibodies. Smoking cessation is essential.

Anti-GBM levels should be monitored periodically until they are negative on two occasions. Approximately half of patients treated with plasmapheresis and immunosuppression will recover, but may be left with renal failure and abnormal lung function.

Patients receiving high dose immunosuppression for any of these conditions are at risk of developing pneumocystis jiroveci infection, so prophylaxis with co-trimoxazole is required. Intravenous fluids can reduce the risk of bladder toxicity, which can occur with intravenous cyclophosphamide.

Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome)

Eosinophilic granulomatosis with polyangiitis (EGPA), or allergic granulomatosis, was previously called Churg-Strauss syndrome. It is a multisystem, autoimmune condition causing inflammation of small and medium-sized blood vessels and usually develops in an individual with a history of atopy. The majority (>90%) have a history of asthma which precedes the development of the vasculitis by approximately 9 years.

In the initial prodromal stage, the majority of patients develop allergic rhinitis presenting with rhinorrhoea, nasal obstruction, nasal polyps, sinusitis, and worsening asthma. Patients may also develop fever and dyspnoea.

This initial stage is followed by marked peripheral blood eosinophilia, with more than 1500 cells ml^-1, or greater than 10% eosinophils on a differential white cell count. This may be masked if the patient is on corticosteroids for asthma.

This stage is followed by an eosinophilic vasculitis, which occurs due to eosinophilic infiltration of organs, causing damage. Eosinophilic infiltration of the lungs results in flitting pulmonary infiltrates on the CXR (see Figure 11.9). An HRCT thorax will show ground-glass changes and patchy areas of consolidation. Symptoms of dyspnoea, wheeze, cough, night sweats, fever, malaise, and weight loss occur.

Infiltration of other organs can result in severe vasculitic complications and infarction of organs. Some 75% of patients develop mononeuritis multiplex, and two-thirds of patients will develop skin involvement, with subcutaneous nodules, granuloma formation, and palpable purpura. Cardiac involvement, which may be asymptomatic, results in myocarditis, cardiomyopathy, and pericardial tamponade, and is fatal in 50% of cases. Myositis, eosinophilic infiltration of the gastrointestinal tract, neuritis, glomerulonephritis, and central nervous system involvement can all occur. Patients with EGPA will have symptoms related to the organs involved as well as systemic symptoms of fever, night sweats, malaise, and weight loss.

Five-year mortality is 12%. Renal involvement, proteinuria, involvement of the central nervous system and gastrointestinal system confer a worse prognosis, with a 5-year mortality rising to 50% if more than two organs are involved.

Diagnosis is made by recognising the clinical presentation, noting the marked peripheral eosinophilia, and demonstrating organ eosinophilia by biopsy of an organ. The lung and skin are most usually biopsied as these are often involved. P-ANCA levels, suggesting antibodies against myeloperoxidase, may be elevated in 40—60% of cases. Box 11.5 lists the American College of Rheumatology criteria for diagnosing EGPA. The presence of at least four of these has a sensitivity of 85% and a specificity of 99.7%.

The main differential diagnosis of EGPA includes allergic asthma, ABPA, granulomatosis with polyangiitis, microscopic polyangiitis and eosinophilic pneumonias. The differential diagnosis of eosinophilic pulmonary disorders is discussed in Chapter 7.

Box 11.5 Diagnosis of EGPA.

• Asthma

• Peripheral eosinophilia >10%

• Mononeuropathy or polyneuropathy

• Flitting pulmonary infiltrates

• Paranasal sinus abnormalities

• Extravascular eosinophils

____

Figure 11.13 CXR showing acute haemorrhage in right lung in a patient with HHT.

Figure 11.14 CXR showing changes of chronic pulmonary haemorrhage.

EGPA responds well to immunosuppression with intravenous corticosteroids, intravenous azathioprine and or cyclophosphamide, although relapse is common. Most patients suffer with chronic disease, with relapses and remissions throughout their lifetime.

Hereditary haemorrhagic telangiectasia (HHT)

Hereditary haemorrhagic telangiectasia (HHT), also called Osler-Weber-Rendau Syndrome, is a vasculitis which presents with multiple pulmonary arteriovenous malformations (AVMs). The exact prevalence is unknown but is estimated to be approximately 1 : 5000 to 1 : 8000.

HHT is an autosomal dominant disorder with mutations of the endoglin, ALK-1 and SMAD4 genes. For a diagnosis to be made, the International Consensus diagnostic criteria require the individual to have a first degree relative with HHT, suffer with spontaneous, recurrent epistaxis, have several mucocutaneous telangiectasias, and have arterio-venous malformations affecting the lungs, brain, liver, or the gastrointestinal tract. Most patients with HHT are asymptomatic in childhood but develop spontaneous and recurrent epistaxis during adolescence. Pulmonary AVMs are abnormal, thin-walled, saccular vessels that connect the pulmonary and systemic circulations. Many individuals with pulmonary AVMs are asymptomatic, but a third can develop clinically relevant right-to-left shunts with hypoxaemia which can progress to heart failure and secondary polycythaemia. These patients will develop clubbing and cyanosis. Pulmonary AVMs can also bleed into the lungs in 1.4%, resulting in haemoptysis and haemothorax, especially in pregnancy. AVMs increase in size during pregnancy, increasing the risk of haemorrhage, with a 1% risk of death (Figure 11.13, Figure 11.14).

The biggest risk is the development of embolic strokes and cerebral abscess secondary to paradoxical embolism. Management of pulmonary AVMs is with embolisation of the vessels to reduce the risk of cerebrovascular accidents. Chapter 5 describes the management of massive haemoptysis.

Individuals with HHT may present with iron deficiency anaemia secondary to gastrointestinal bleeding and with cerebral haemorrhage. It is important to screen family members to identify those at risk. There is some evidence that hormones and antifibrinolytic agents reduce the risk of gastrointestinal and nasal haemorrhage. Patients who suffer recurrent epistaxis, haemoptysis and haemo- thorax are advised not to embark on air travel.

■ Thromboembolic disease is common in patients admitted to hospital, with 1% developing deep vein thrombosis and/or pulmonary emboli.

■ Patients who are admitted to hospital should be assessed for their risk of developing VTE and offered prophylactic LMWH as appropriate.

■ Acute pulmonary embolus should always be in the differential diagnosis of any patient presenting with acute breathlessness, pleuritic chest pain, unexplained hypoxia, hypotension, or collapse.

■ The modified Wells score should be used to determine the probability of the patient having VTE.

■ A CTPA is usually used to confirm the diagnosis of pulmonary embolus.

■ Patients who present with acute pulmonary embolus should receive anticoagulation with low molecular weight heparin and warfarin or a NOAC.

■ Patients who develop massive, life-threatening pulmonary embolus and who are haemodynamically unstable may require thrombolysis.

■ Patients who develop pulmonary embolus without an obvious risk factor should receive anticoagulation indefinitely.

■ Chronic thromboembolic disease should be considered in anyone presenting with insidious dyspnoea.

■ A VQ scan is the investigation of choice for patients suspected of having chronic pulmonary emboli.

■ Patients with acute or chronic pulmonary emboli can develop pulmonary arterial hypertension.

■ Pulmonary hypertension is defined as a mean pulmonary artery pressure of greater than 25 mmHg.

■ There are many different causes of pulmonary hypertension.

■ Pulmonary arterial hypertension has a bad prognosis with a mean life expectancy of 3 years without treatment.

■ A definitive diagnosis of pulmonary hypertension is made with a right heart catheter which directly measures the PAP and the response to vasodilators.

■ Management of PH is with treatment of the underlying cause, anticoagulation, calcium antagonists (in some cases), and LTOT.

■ Patients with pulmonary arterial hypertension and WHO functional class III or IV must be assessed in a specialist centre and receive advanced treatments.

■ Pulmonary haemorrhagic syndromes can affect many organs and may present with life-threatening haemoptysis.

■ Most of these conditions are ANCA- positive and respond well to immunosuppression and plasmapheresis.

■ Hereditary haemorrhagic telangiectasia is an inherited condition with the development of AVMs which can present with haemorrhage into the lungs, brain, and gastrointestinal system.

MULTIPLE CHOICE QUESTIONS

11.1 Which of the following statements about acute pulmonary emboli is true?

A A CXR is a sensitive test in making a diagnosis of PE

B ECG changes can be used to make a diagnosis of PE

C Patients with a PE always present with symptoms of breathlessness

D Symptoms of PE always occur within minutes of occlusion of the pulmonary artery E About 70% of patients with a PE will be hypoxaemic

Answer: E

PE often presents with non-specific symptoms which can occur within minutes,

although many patients present after days, weeks or months. Only 73% of patients with a PE present with symptoms of breathlessness. Neither a CXR or ECG changes are specific for PE and can be confidently used to make a diagnosis of a PE on their own.

11.2 Which of the following statements about the diagnosis of PE is true?

A A positive D-dimer level is helpful in making a diagnosis of PE

B A normal troponin level means that a PE can be ruled out

C A modified Wells score, used together with imaging and D-dimer level, increases the sensitivity of the test

D VQ scan is the imaging modality of choice in most patients

E Patients with a high Wells score and negative D-dimer will not require any further investigations

Answer key: C

The D-dimer level may be high for many reasons so cannot be used to make a diagnosis of PE. A negative D-dimer in a patient with a low Wells score rules out PE. Troponin may be elevated in patients with a large PE, but cannot be used to exclude PE. CTPA is the main imaging modality for PE, with a higher sensitivity and specificity than VQ scan and because it is available in most centres. Patients with a high clinical probability of PE will require further investigations (CTPA) regardless of the D-dimer result.

11.3 Which of the following statements about acute PE is true?

A All patients presenting with an acute PE should be hospitalised

B Patients with an acute PE should be started on warfarin as the first anticoagulant

C LMWH is the initial treatment of choice for most haemodynamically stable patients with PE

D Patients who are hypotensive should be commenced on LMWH

E Rivaroxaban is the treatment of choice for patients with severe PE

Answer: C

Patients who are haemodynamically stable and not hypoxaemic can be anticoagulated safely at home. The guidelines recommend that patients with acute PE are started on LMWH first, which should be continued for at least 48 hours after the INR level is therapeutic. Patients with severe PE and hypotension should be given IVUFH as they may require thrombolysis, and UFH has a shorter half-life and the effects can be reversed more quickly. Rivoroxaban, a Factor Xa inhibitor, is contra-indicated as the effects cannot be easily reversed.

11.4 Which of the following statements is true?

A All patients with acute PE should be anticoagulated for 12 months

B Patients who develop PE after surgery should be anticoagulated for 6 months

C Patients with recurrent PEs should be anticoagulated for life

D The risk of PE recurrence is 5% in the first 5 years

E Most patients who have a PE are found to have a DVT

Answer: C

The recommendations are that patients with a known specific cause for the PE, such as surgery, should receive 3 months of anticoagulation. If the cause is unknown, then they should receive 6 months and then be reviewed. The risk of recurrence is up to 20% over the first 5 years, so patients with unprovoked or recurrent PEs may need lifelong anticoagulation. Only 10% of patients with PE are found to have a DVT.

11.5 Which of the following statements about chronic thromboembolic disease (CTED) is true?

A Patients with CTED should receive intravenous prostacyclin

B Thrombolysis is the treatment of choice for those with CTEPH

C Some 50% of patients with acute PE develop CTED

D A diagnosis of CTED can be made with an echocardiogram

E Embolectomy should be considered in a patient with CTEPH

Answer: E

Only 1—5% of patients with acute PE go on to develop CTED, but the majority of these will have evidence of pulmonary hypertension which requires a right heart catheter for a definitive diagnosis. Embolectomy is often successful in these patients where neither prostacyclin or thrombolysis is indicted.

11.6 Which of the following statements about pulmonary hypertension is true?

A Hereditary pulmonary hypertension is the commonest aetiology

B Median survival of Group 1 PAH is 10 years without treatment

C Group 1 PAH has a worse prognosis than the other types of PH

D Some 50% of those who survive an acute pulmonary embolus develop PH

E The diagnosis of pulmonary hypertension can be made rapidly in the clinic

Answer: C

Hereditary (familial) pulmonary hypertension accounts for a minority of all cases of pulmonary hypertension. Group 1 PAH has the worst prognosis, with a median survival of 3 years without treatment. Some 1—5% of patients who survive an acute pulmonary embolus develop pulmonary hypertension. The diagnosis of pulmonary hypertension can be difficult as the symptoms are often vague and insidious. There is evidence that it can take more than 2 years before a definitive diagnosis is made.

11.7 Which of the following is consistent with a diagnosis of pulmonary hypertension?

A Mean PAP > 15 mmHg at right heart catheter

B Increased pulmonary vasculature on CXR

C ECG showing ST elevation in the anterior leads

D Pan-systolic murmur throughout the praecordium

E Enlarged right ventricle on transthoracic echocardiogram

Answer: E

Patients with pulmonary hypertension will have pruning of the pulmonary vessels on CXR, ECG will show tall p wave in leads II,

IV, AVF (p pulmonale) with a tall R wave in V1, ST segment depression with T wave inversion in V1—V3. The mean PAP will be greater than 25 mmHg at rest or greater than 30 mmHg on exertion. A pan-systolic murmur is not associated specifically with pulmonary hypertension.

11.8 Which of the following is NOT indicated as management of established Group 1 pulmonary arterial hypertension?

A Endothelin inhibitor

B Fibrinolytic agent

C Heart lung transplantation

D Phosphodiesterase-5 inhibitor

E Prostacyclin analogues

Answer: B

Fibrinolytic agents are not indicated in the management of PAH. All the others are indicated.

11.9 Which of the following statements about granulomatosis with polyangiitis (GPA) is true?

A Relapse is commoner in those with upper airway and lung involvement B GPA commonly presents with nephritic syndrome

C A history of atopy is uncommon in patients with GPA

D Nasal involvement is rare with GPA

E Majority of patients with GPA will be p-ANCA positive

Answer: A.

Most patients with GPA are c-ANCA positive and present with necrotising glomerulonephritis. Nasal involvement is common, and relapse is commoner in those with upper airway and lung involvement. History of atopy is common in those with Eosinophilic granulomatosis with polyangiitis and not in GPA.

11.10 Which of the following statements about hereditary haemorrhagic telangiectasia (HHT) is NOT true?

A HHT is an autosomal recessive disorder

B HHT increases the risk of cerebrovascular accidents secondary to paradoxical embolism

C HHT increases the risk of haemoptysis and haemothorax in pregnancy

D Most patients with HHT are asymptomatic in childhood

E Iron deficiency anaemia can occur secondary to gastrointestinal bleeding

Answer: A

HHT is an autosomal dominant disorder.

Arteriovenous malformations (AVMs)

develop in many organs, including the lungs, the brain, and the gastrointestinal tract which can bleed, resulting in haemoptysis cerebrovascular accidents and gastrointestinal bleeding. HHT can present with iron-deficiency anaemia. The risk of bleeding is increased in pregnancy. Children are relatively asymptomatic, and symptoms develop progressively after puberty.