Pulmonary Embolism

Background

Epidemiology

Pulmonary embolism (PE) is the third most common cardiovascular disease, with an incidence of approximately 60-70 per 100,000 people (1). The vast majority occur provoked, with common risk factors including deep venous thrombosis (DVT) elsewhere, underlying active malignancy, prolonged immobility, recent surgery, lower limb trauma, inherited and acquired thrombophilias, use of the combined oral contraceptive pill (COCP), pregnancy and obesity. 

Pathophysiology

Pulmonary embolism (PE) is a form of venous thromboembolism (VTE) affecting the pulmonary arterial system and can be either an acute or chronic problem associated with the risk factors detailed above. It most commonly occurs when emboli from elsewhere in the deep venous system travel to the pulmonary vasculature and become lodged in a pulmonary artery. This results in a ventilation-perfusion mismatch, as healthy lung tissue is insufficiently perfused with oxygenated blood and can cause progression to pulmonary infarction. Less commonly, non-thrombotic sources of emboli can arise, including air emboli, fat emboli, septic emboli and, in pregnant women, amniotic fluid emboli. In severe cases, PE can be associated with hypotension, syncope and sudden death, as pulmonary arterial pressure increases to the point where it causes right ventricular failure and compromises cardiac output. 

Presentation

Clinical features of pulmonary embolism most commonly include tachypnoea, pleuritic chest pain, tachycardia, cough and haemoptysis. Features of the underlying cause are often present, in particular, unilateral lower limb pain and swelling in the case of DVT. Symptoms indicating severe illness include pre-syncope and syncope. Symptoms and signs on examination are important to elicit if present, as they form the basis of several scoring systems, such as the Wells’ score and PERC rule (see diagnosis section). 

Common examination signs in PE (2):

• Tachycardia >100bpm
• Tachypnoea
• Hypoxia
• Hypotension
• Elevated jugular venous pressure (JVP)
• Loud P2 
• Pleural rub 

Diagnosis

PE should be part of the differential diagnosis in any adult presenting with chest pain, although it cannot be diagnosed on the basis of clinical history and examination alone. The diagnostic pathway followed depends on pre-test clinical probability; several clinical scoring tools have been developed to aid in this diagnostic process. 

Clinical scoring tools

Wells’ score for PE 

A risk stratification tool that determines recommended further investigations when used in the presence of clinical suspicion of PE. A score of >4 indicates that PE is likely and the clinician should proceed directly to CT pulmonary angiogram (CTPA), whilst a score of 4 or less suggests PE is less likely and that a d-dimer blood test should first be performed. If the d-dimer result is then negative, PE can be ruled out, whilst a positive d-dimer result would indicate further investigation +/- treatment is required. 

Table 1 – Wells’ score for PE. 

Criteria	Points if present
Clinical signs and symptoms of DVT	3
PE is the number one diagnosis OR equally likely	3
Heart rate >100	1.5
Immobilisation for at least 3 days OR surgery in the previous 4 weeks	1.5
Previous, objectively diagnosed PE or DVT	1.5
Haemoptysis	1
Malignancy within 6 months of treatment OR palliative	1

Pulmonary Embolism rule-out criteria (PERC score)

The PERC score is strictly a rule-out criteria in patients who have a low pre-test probability of PE. When used in the correct patient group, a PERC score of 0 indicates the clinician can safely rule out a PE without the need for further investigations. Scoring even a single point means the PERC rule cannot be used to rule out PE, but importantly, it cannot be used to make a positive diagnosis in itself. 

Table 2 – PERC rules.

Age ≥ 50	1
Heart rate ≥ 100 bpm	1
Oxygen saturations on room air <95%	1
Unilateral leg swelling	1
Haemoptysis	1
Recent surgery or trauma requiring general anaesthesia ≤ 4 weeks ago	1
Prior PE or DVT	1
Hormone use	1

Table 1 Source: Wells’ Criteria for DVT – MDCalc [Internet]. Available from: https://www.mdcalc.com/wells-criteria-dvt

Table 2 Source: PERC Rule for Pulmonary Embolism – MDCalc [Internet]. Available from: https://www.mdcalc.com/perc-rule-pulmonary-embolism

Investigations

• Blood tests
  • Full blood count (FBC)
  • Clotting screen
  • Urea and electrolytes (U&Es) – important in particular when considering whether the patient is fit for a CTPA with contrast 
  • D-dimer – only to be used in patients with a low pre-test probability 
  • Troponin – to help risk stratify 
• Arterial blood gas sampling – look for hypoxia and hypocapnia 
• Electrocardiogram (ECG) – features include:
  • Sinus tachycardia
  • Right bundle branch block (RBBB)
  • S1Q3T3 – Deep S-waves in lead I, pathological Q-waves in lead III, inverted T-waves in lead III  
  • T-wave inversion in V1-V3 (right ventricular strain pattern)
  • P pulmonale 

Image Source: Wikimedia Commons (2010). Pulm_embolism, Licensed under a creative commons licence. Available for free at: https://commons.wikimedia.org/wiki/File:Pulm_embolism.jpg (Accessed: 5 June 2022).

• Imaging 
  • Chest x-ray (CXR)– useful to exclude alternative diagnoses, and a normal CXR is also a prerequisite for interpreting a ventilation/perfusion (V/Q) scan.
  • CT pulmonary angiogram (CTPA) – the main imaging modality of choice to look for filling defects associated with large or subsegmental PEs.
  • Ultrasound doppler – not a direct diagnostic test for PE, but sometimes used to identify lower limb DVTs in patients where ionising radiation is contraindicated (i.e., in pregnancy). If a VTE elsewhere is identified, and the patient has the classical signs and symptoms, treatment can be started empirically.
  • Ventilation/perfusion (V/Q) scanning – imaging using radioisotopes to identify any areas of mismatch in ventilation and perfusion of the lungs.
  • Transthoracic echocardiogram – not part of the formal diagnostic pathway, but can be used as adjunctive imaging to identify features of right heart strain, such as right ventricular dilatation and a poorly compressible internal vena cava (IVC) (3).

Image Source: Wikimedia Commons (2007). Pulmonary embolism CTPA, Licensed under a creative commons licence. Available for free at: https://commons.wikimedia.org/wiki/File:Pulmonary_embolism_CTPA.JPEG (Accessed: 5 June 2022).

Differential diagnoses

Pulmonary embolism is a life-threatening diagnosis which is important not to miss. There is a broad differential for both chest pain and shortness of breath, and symptoms and signs can be shared with a multitude of other conditions. We will focus mainly on other diagnoses; it would be important to differentiate from PE due to comparable clinical urgency. 

Acute coronary syndrome

Acute coronary syndrome is a term that encompasses patients presenting with unstable angina, non-ST-elevation and ST-elevation myocardial infarction. Classical symptoms include chest pain or tightness, shortness of breath, diaphoresis, nausea, vomiting and dizziness. PE shares a lot of similar features, although generally has a greater association with hypoxia and tachycardia, and the nature of the chest pain is classically described as more pleuritic. ECG would be a mainstay of differentiating between the two diagnoses – if this raised significant clinical suspicion of a myocardial infarction, the patient would need to be taken for urgent cardiac catheterisation. Blood tests can help guide diagnosis, but caution should be used when relying on biochemical markers alone, as troponin and d-dimer can be deceptively raised in both conditions. 

Pneumothorax

Primary, secondary and tension pneumothoraces can all present with sudden onset pleuritic chest pain and shortness of breath. A past medical history of pre-existing airways disease may point towards a diagnosis of secondary pneumothorax, but overall, few features in the history alone can differentiate between pneumothorax and pulmonary embolism. On examination, the most notable feature would be reduced breath sounds and hyperresonance to percussion on the side of a pneumothorax, as well as tracheal deviation in the case of a tension pneumothorax. Comparably, air entry should sound normal in a PE. In many cases, definitive treatment will involve chest drain insertion, so early access to chest radiograph imaging for diagnosis is essential. 

Pericarditis

Pericarditis classically presents with chest pain relieved on leaning forwards, shortness of breath and sometimes dizziness. Similarly to a PE, it can present in a young population in the absence of a clear trigger. Features that raise suspicion of pericarditis would include a clear history of recent viral infection, co-existing inflammatory disorders such as rheumatoid arthritis or a fever at presentation itself. ECG features also include widespread saddle-shaped ST-elevation. It is important to keep in the differential as the life-threatening complication of pericardial effusion can occur. 

Aortic dissection

Aortic dissection is a medical emergency that causes sudden onset, severe, tearing chest pain that often radiates to the back. Classical features on examination include a wide pulse pressure and radial-radial or radial-femoral delay. Definitive diagnosis can only be made by CT aortogram imaging, so a high index of suspicion must be maintained when reviewing any patient presenting with chest pain, particularly patients with a past medical history of aortic aneurysm or hypertension. 

Other disorders

As shortness of breath, pleuritic chest pain, cough and haemoptysis are common presentations associated with a range of clinical conditions, the differential must be kept broad and guided by findings on history and examination. Any respiratory disorder such as pneumonia, lung cancer or pleural effusion could potentially be a mimic of a PE. Equally, musculoskeletal causes of chest pain, such as costochondritis or Tietze’s syndrome, can commonly produce pain of a similar nature, but these must remain a diagnosis of exclusion (4). 

Management 

The first step of managing an acute PE involves a similar approach to any other acute medical scenario by assessing the patient in an ABCDE fashion, identifying and treating features such as hypoxia and hypotension. Once the patient has been stabilised, it is important to risk stratify patients into low, intermediate and high-risk categories. The Pulmonary Embolism Severity Index (PESI) and, later, the simplified PESI (sPESI) have been developed to help clearly delineate risk by calculating 30-day mortality. This should be calculated for any patient presenting with a confirmed PE, unless there is clear evidence of haemodynamic compromise on presentation, in which case a medical emergency algorithm approach should be taken to proceed immediately to thrombolysis. An sPESI score of one or more indicates the patient is at least intermediate risk and should be managed as an inpatient. If the sPESI score is zero, in some scenarios, the patient can be managed on an ambulatory basis (5). 

High-risk features in PE:

• Haemodynamic instability – persistent hypotension <90mmHg or a systolic drop of ≥40mmHg lasting for 15 or more minutes, not caused by new-onset arrhythmia, hypovolaemia or sepsis. 
• sPESI score of  ≥1
• Features of right ventricular dysfunction on TTE or CTPA
• Elevation of cardiac troponin levels 

Table 3 – sPESI score.

Criteria	Score
Age >80	1
History of cancer	1
History of chronic cardiopulmonary disease	1
Heart rate ≥ 110bpm	1
Systolic blood pressure <100mmHg	1
O2 saturation <90%	1

Table 4 – Recommendations for anticoagulation in PE

Reperfusion treatment

• Systemic thrombolysis – for patients with features of haemodynamic compromise as defined above (‘massive PE’), intravenous thrombolysis can be undertaken with agents such as recombinant tissue-type plasminogen activator (alteplase) or streptokinase, in the absence of major bleeding risk factors.
• Catheter-directed thrombolysis – there is growing use of targeted thrombolysis therapy and mechanical thrombectomy using percutaneous approach via pulmonary artery catheterisation.
• Surgical embolectomy – open embolectomy of the pulmonary artery clots requiring cardio-pulmonary bypass (7).

Supportive management 

• Respiratory support is often required in PE, ranging from nasal cannulae and simple face mask oxygen support to invasive ventilation and, rarely, extracorporeal membrane oxygenation (ECMO). 
• Haemodynamic support – intravenous fluids, and in some cases, vasopressor and inotropic support. 
• Multidisciplinary pulmonary embolism response teams (PERTs) – there is a growing use of MDTs comprising members from various disciplines, including cardiology, haematology and interventional radiology, amongst others, to make clinical decisions on optimal PE management on an individual basis.

Reperfusion treatment

• Systemic thrombolysis – for patients with features of haemodynamic compromise as defined above (‘massive PE’), intravenous thrombolysis can be undertaken with agents such as recombinant tissue-type plasminogen activator (alteplase) or streptokinase, in the absence of major bleeding risk factors.
• Catheter-directed thrombolysis – there is growing use of targeted thrombolysis therapy and mechanical thrombectomy using percutaneous approach via pulmonary artery catheterisation.
• Surgical embolectomy – open embolectomy of the pulmonary artery clots requiring cardio-pulmonary bypass (7).

Supportive management 

• Respiratory support is often required in PE, ranging from nasal cannulae and simple face mask oxygen support to invasive ventilation and, rarely, extracorporeal membrane oxygenation (ECMO). 
• Haemodynamic support – intravenous fluids, and in some cases, vasopressor and inotropic support. 
• Multidisciplinary pulmonary embolism response teams (PERTs) – there is a growing use of MDTs comprising members from various disciplines, including cardiology, haematology and interventional radiology, amongst others, to make clinical decisions on optimal PE management on an individual basis.

Internal vena cava filters 

In patients where anticoagulation in PE is absolutely contraindicated, insertion of an internal vena cava (IVC) filter can be considered. Theoretically, these prevent recurrent PEs from occurring by mechanically blocking the travel of potential venous thromboemboli into the proximal circulation. Whilst they do decrease risk of recurrent PE, they are actually associated with a significantly increased risk of DVT, likely due to instrumentation in the absence of anticoagulation, and thus have no mortality benefit overall. 

References

• Pathophysiology | Background information | Pulmonary embolism | CKS | NICE [Internet]. Cks.nice.org.uk. 2022 [cited 4 March 2022]. Available from: https://cks.nice.org.uk/topics/pulmonary-embolism/background-information/pathophysiology/
• Hall T. PACES for the MRCP. Saint Louis: Elsevier Health Sciences UK; 2014.
• Elyas A. [Internet]. Escardio.org. 2022 [cited 4 April 2022]. Available from: https://www.escardio.org/static-file/Escardio/Subspecialty/EACVI/Education/Teaching%20courses/2019/Use%20of%20echocardiography%20in%20diagnosis%20of%20pulmonary%20embolism.pdf
• Thompson B, Kabhrel C, Pena C. UpToDate [Internet]. Uptodate.com. 2022 [cited 4 June 2022]. Available from: https://www.uptodate.com/contents/clinical-presentation-evaluation-and-diagnosis-of-the-nonpregnant-adult-with-suspected-acute-pulmonary-embolism#H746822394
• Tapson V, Weinberg A. UpToDate [Internet]. Uptodate.com. 2022 [cited 4 April 2022]. Available from: https://www.uptodate.com/contents/treatment-prognosis-and-follow-up-of-acute-pulmonary-embolism-in-adults
• Provoked versus unprovoked pulmonary embolism (PE) or deep vein thrombosis (DVT) – General Practice Notebook [Internet]. Gpnotebook.com. 2018 [cited 4 April 2022]. Available from: https://gpnotebook.com/en-gb/simplepage.cfm?ID=x20120725074001799563
• Konstantinides S, Meyer G, Becattini C, Bueno H, Geersing G, Harjola V et al. 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS). European Heart Journal. 2019;41(4):543-603.

Pulmonary Hypertension

Background

Epidemiology

Pulmonary hypertension is defined as an increase in pulmonary artery pressure (PAP) to more than 25mmHg at rest when measured on right heart catheterisation studies. Comparatively, the average PAP in a healthy individual is around 14mmHg (1). Due to formal diagnosis relying on this invasive testing, we can assume that case numbers are largely underreported on a global scale. In the U.K., incidence is reported as 97 cases per million, with a slightly increased prevalence in females.  

Pathophysiology

Pulmonary hypertension is a broad term which encompasses five distinct aetiological categories. The pathophysiology of all subcategories is defined by an increased pulmonary vascular resistance, resulting in progressively increased pulmonary artery pressures and eventually right ventricular failure and death. The disease course generally follows a progressive deterioration interspersed with acute episodes of decompensation. 

The World Health Organisation (WHO) has classified pulmonary hypertension into five groups (2):

• Group 1 – Pulmonary Arterial Hypertension (PAH) – defined by sustained vascular remodelling of the pulmonary arteries. There are a range of causes, including:
  • Idiopathic 
  • Inherited – account for approximately 10% of cases, most commonly associated with a mutation in the BMPR2 gene
  • Drugs and toxins, such as fenfluramine
  • Congenital heart disease associated with left-right shunting, e.g., ASD, VSD
  • Connective tissue diseases
  • Vasculitis
  • Human Immunodeficiency Virus (HIV) 
  • Schistosomiasis 
  • Pulmonary veno-occlusive disease
• Group 2 – Pulmonary hypertension secondary to left heart disease is thought to be the most common subgroup due to the frequency of left heart disease. Pathophysiology involves the passive backflow of blood from a poorly functioning left-sided system (due to either systolic, diastolic or valvular dysfunction), causing increased right-sided pressures. Causes include:
  • Left ventricular systolic dysfunction
  • Left ventricular diastolic dysfunction
  • Valvular disease
  • Congenital or acquired left ventricular inflow or outflow tract obstruction, such as hypertrophic obstructive cardiomyopathy (HOCM)
  • Congenital or acquired pulmonary venous stenosis 
• Group 3 – Pulmonary hypertension due to lung diseases and/or hypoxaemia. Hypoxia induces vasoconstriction and endothelial cell damage and remodelling via neo-muscularisation and collagen deposition. Causes include:
  • Interstitial lung disease – often associated with severe PH
  • Chronic Obstructive Pulmonary Disease (COPD) – commonly associated with mild PH
  • Obstructive sleep apnoea
  • Alveolar hypoventilation disorders
  • Chronic exposure to high-altitude
  • Neuromuscular causes such as myasthenia gravis and motor neurone disease 
• Group 4 – Chronic thromboembolic pulmonary hypertension (CTEPH) is associated with prolonged occlusion of the pulmonary vasculature, most typically by a thrombus. Sometimes occurs when a pulmonary embolism has not been diagnosed and treated in the acute setting, but can also be due to poor resolution of thrombi despite anticoagulant treatment. Rarely, can also occur with other pulmonary artery obstructions such as angiosarcoma or hydatid cyst disease. 
• Group 5 – Pulmonary hypertension with unclear and/or multifactorial mechanism, including:
  • Haematological, e.g., sickle cell disease, myeloproliferative diseases, chronic haemolytic anaemia
  • Systemic, e.g., sarcoidosis, neurofibromatosis, pulmonary histiocytosis 
  • Metabolic disorders, e.g., Gaucher’s disease, thyroid disease, disorders of glycogen storage
  • Others, e.g., pulmonary capillary haemangiomatosis, fibrosing mediastinitis, chronic renal failure

Presentation 

Symptoms

Symptoms of pulmonary hypertension can be non-specific and most commonly include fatigue, shortness of breath, angina and syncope. These symptoms are all classically worse on exertion, and severity of symptom burden is often assessed for these patients by calculating their MRC Dyspnoea Scale score (grading breathlessness on a scale of 0-4). Structural complications of the disease can also result in further symptoms such as haemoptysis (due to bronchial artery rupture) and hoarseness of voice (due to compression of the left recurrent laryngeal nerve). 

Clinical signs

• Right ventricular heave
• Central cyanosis 
• Peripheral oedema
• Ascites
• Loud P2 
• Pansystolic murmur heard loudest at the left lower sternal edge (secondary to tricuspid regurgitation)
• Elevated jugular venous pressure 
• Lancisi’s sign (giant C-V waves seen in tricuspid regurgitation)

Take care to also observe for clinical signs on examination that may point you towards the underlying diagnostic cause of the pulmonary hypertension, such as digital clubbing or telangiectasia (3). 

Diagnosis 

Once there is clinical suspicion of pulmonary hypertension, patients are often referred to a regional specialist pulmonary hypertension centre for focused investigation and access to a multidisciplinary approach. Depending on the level of clinical suspicion, there are many investigations that can be undertaken.

Investigations

• Blood tests, including FBC, U&E, LFT, TFTs, a full autoimmune screen and thrombophilia screening – whilst these are not diagnostic, they can point towards the aetiology. NT-proBNP is also measured and used as an independent marker of severity in pulmonary hypertension.
• Electrocardiogram (ECG) – can often be normal, but ECG changes associated with right ventricular strain are common, including p pulmonale, right axis deviation, right bundle branch block and QTc prolongation. In advanced disease, there is often also an association with atrial arrhythmias. 
• Chest radiograph – can show features of right atrial and ventricular enlargement, pulmonary arterial dilatation as well as clues to the underlying cause of the pulmonary hypertension.
• Pulmonary function tests – most commonly, patients with pulmonary hypertension have a reduced carbon monoxide lung diffusion capacity (transfer factor, or TLCO). Obstructive and restrictive defects from co-existing or related airways or interstitial lung disease can also aid with diagnosis but are best interpreted in the context of cross-sectional imaging. 
• Arterial blood gas 
• Transthoracic echocardiography – can be used to support a diagnosis of pulmonary hypertension, but, like all of the above tests, is not strictly diagnostic. Peak tricuspid regurgitation velocity is used as a substitute marker for pulmonary arterial pressures – a value of >3.4m/s is highly suggestive of the diagnosis. Other suggestive features include right atrial and ventricular dilatation, pulmonary regurgitation and flattening of the interventricular septum.
• Ventilation/perfusion scan – identifies patients with unmatched perfusion defects as the underlying cause of pulmonary hypertension, indicating CTEPH
• High-resolution computed tomography and pulmonary angiography (HRCT/CTPA) – cross-sectional imaging can reveal features of pulmonary hypertension, such as right ventricular or pulmonary artery dilatation, but is also essential in investigating the underlying cause, such as lung disease or CTEPH. CTPA can help identify the subset of patients with CTEPH who may benefit from intervention with pulmonary endarterectomy. 
• Cardiac magnetic resonance imaging (CMRI) – provides detailed assessment of the right ventricular structure as well as function, which can strongly support a diagnosis of pulmonary hypertension but cannot be used to exclude it.
• Abdominal ultrasound scan – to look for the complication of portal hypertension
• Right heart catheterisation – this is the gold standard test for diagnosis. It allows for direct measurement of pulmonary arterial pressures and oxygen saturation levels within the internal vena cava. Left heart catheterisation is often performed at the same time, as it is a requirement for patients likely to proceed to pulmonary endarterectomy, and can be useful diagnostically in patients where left heart disease is a suspected cause. 
• 6-minute walking test – used as a marker of severity once the diagnosis has been made. Measures simply the maximum walking distance a patient achieves in the set 6-minute time frame. 
• Cardiopulmonary exercise testing (CPET)

Management

Group 1 – Pulmonary Arterial Hypertension 

Supportive

• Oral anticoagulation is indicated due to increased risk of VTE in this patient group
• Supplemental oxygen as required to aim of pO2 >8kPa
• Correct iron deficiency anaemia 
• Diuretic therapy for clinically fluid-overloaded patients 
• Treatment of co-existing atrial arrhythmias; digoxin is often the drug of choice 
• Counsel patients regarding substantial mortality associated with pregnancy and offer appropriate birth control
• Offer routine influenza and pneumococcal vaccinations
• Encourage physical activity within symptom limits

Disease-modifying pharmacological therapy, used as both monotherapy and in combination:

• Calcium channel blocker therapy
  • Both dihydropyridine (amlodipine; nifedipine) and non-dihydropyridine (diltiazem) CCBs are used, depending on baseline heart rate. 
  • Can be used only in patients shown to be responsive to vasodilator therapy when tested during right heart catheterization
• Endothelin receptor antagonists
  • Work by interfering with the endothelin pathway, blocking pulmonary vascular smooth muscle vasoconstriction
  • Taken as oral agents, they have been shown to improve exercise capacity as well as echocardiographic and haemodynamic measurements. 
  • Examples include bosentan, ambrisentan (both of which require monthly liver function test monitoring) and macitentan
• Phosphodiesterase type 5 inhibitors 
  • Work by preventing degradation of the enzyme cyclic guanosine monophosphate (cGMP), resulting in pulmonary vasodilation 
  • Examples include sildenafil, tadalafil and vardenafil, all of which are oral agents originally approved for use in erectile dysfunction. 
  • Shown to improve exercise tolerance as well as echocardiographic and haemodynamic measurements 
• Prostacyclin analogues and prostacyclin receptor agonists
  • Endothelial cells produce prostacyclin, which acts as a potent vasodilator of the pulmonary vascular bed. Synthetic prostacyclins have the same effect. 
  • Epoprostenol is a synthetic prostacyclin, which is the only treatment shown to have a mortality benefit when used in idiopathic PAH (although other similar agents include iloprost and treprostinil). The half-life of epoprostenol is very short, at only 3-5 minutes, necessitating it to be administered as a continuous IV infusion, which should not be abruptly stopped. This is associated with infection risks of having a long-term central venous catheter in situ, as well as a side effect profile of flushing, diarrhoea, headache and jaw pain. 
  • Selexipag is an oral prostacyclin receptor agonist proven to reduce pulmonary arterial hypertension.

Interventional

• Balloon atrial septostomy – the intentional creation of an atrial septal defect to allow for right-to-left shunting and decompression of the high-pressure right heart and increase cardiac output. This procedure is used very rarely, either as a palliative measure or bridge to lung transplant.
• Lung transplantation – bilateral lung transplantation in PAH patients can have up to 75% 5-year survival rates.
• Bronchial artery embolisation – can be used to symptomatically control severe haemoptysis.

Group 2 – pulmonary hypertension due to left heart disease 

The primary goal of treatment here is to optimise the underlying condition, for example, valve replacements or heart failure therapies where indicated. The use of specific therapies approved in PAH is not evidenced in group 2 disease. 

Group 3 – pulmonary hypertension due to lung disease

Appropriate treatment of the primary lung disease, with additional oxygen supplementation for hypoxaemia, is the goal of treatment. Similarly to group 2 disease, there is no evidence for the effectiveness of any disease-modifying therapy in this subtype. 

Group 4 – chronic thromboembolic pulmonary hypertension

Medical

Lifelong anticoagulation is the mainstay of medical management for CTEPH, even if surgical intervention takes place. In patients deemed not fit for surgical intervention, anticoagulation alone is recommended. 

Surgical

Pulmonary endarterectomy is the gold-standard treatment of choice for CTEPH. There is proven to be a substantial benefit both symptomatically and haemodynamically post-operatively, with patients debilitated by breathlessness often able to return to normal functioning. However, the procedure is performed with the patient in a hypothermic state under induced circulatory arrest, so not all CTEPH patients would be appropriate candidates. In patients with co-existing coronary artery disease, bypass grafting can be performed simultaneously. 

Group 5 – pulmonary hypertension with unclear or multifactorial aetiology

Like with group 2 and group 3 cases, the primary aim should be rigorous diagnostic investigations to try and establish the underlying cause and treat this accordingly. There are no specific disease-modifying therapies in this group.

References

• Galiè N, Humbert M, Vachiery J, Gibbs S, Lang I, Torbicki A et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. 2022.
• Sysol J, Machado R. Classification and pathophysiology of pulmonary hypertension. Continuing Cardiology Education. 2018;4(1):2-12.
• Kalra P. Essential revision notes for MRCP. Knutsford, Cheshire: PasTest; 2014.

Acute Respiratory Distress Syndrome

Background

Acute respiratory distress syndrome (ARDS) is defined by the acute onset of lung inflammation, causing a diffuse, non-cardiogenic pulmonary oedema and respiratory failure. Due to the nature of the diagnostic criteria, it is almost exclusively a diagnosis made and managed in a critical care setting. 

Epidemiology

There are various estimates for the prevalence of ARDS, ranging from 1 case per 100,000 to 79 per 100,000. One large, multi-centre study projected incidence as 86 per 100,000 person-years. Prevalence in the intensive care patient population is thought to be around 10%, rising to 23% in the mechanically ventilated patient group. Mortality from ARDS is estimated to be around 40%, increasing depending on severity group. It can affect many different patient groups, but incidence increases with age (1).

Pathophysiology

ARDS is an umbrella term encompassing multiple different disease processes leading to a distinct clinical syndrome. The most common causes are sepsis, pneumonia (including COVID-19 pneumonitis), aspiration, trauma, pancreatitis and transfusion of blood products. All causes of ARDS result in an increased vascular endothelial permeability, allowing for accumulation of protein-rich fluid in the alveolar spaces. This initiates the release of pro-inflammatory cytokines, such as Tumour Necrosis Factor (TNF), IL-1 and IL-6, creating a further cycle of damage, whereby neutrophils are recruited to accumulate in the alveolar spaces, and toxic free radical production causes extensive oxidative cell damage. This diffuse alveolar damage results in impaired gas exchange, reduced lung compliance and pulmonary hypertension (2).

The pathophysiology of ARDS can be divided into three distinct stages (3):

• Early exudative stage – the acute reaction to lung injury from various sources, involving inflammation and alveolar oedema. This lasts for around 7-10 days. 
• Fibroproliferative stage – remodelling of the alveolar cell walls with fibroblastic invasion and collagen deposition, reducing compliance. 
• Fibrotic stage – not all patients progress to this final stage. It involves the complete destruction of the alveolar architecture, with cyst formation and further fibrosis. 

Presentation

Signs and symptoms

Symptoms of ARDS can be non-specific but include shortness of breath, dry cough, fever, confusion, myalgia, dizziness and fatigue. Patients may often have many of the above symptoms due to their underlying diagnosis, so regular and close monitoring is key in early identification of progression to ARDS. On examination, features include tachypnoea, tachycardia, diffuse crepitations on auscultation and cyanosis, depending on severity. Signs of acute pulmonary oedema, such as raised JVP and peripheral oedema, should be absent.

Diagnosis

To diagnose ARDS, the following clinical and radiographic criteria need to be met (4):

• Acute onset time of <1 week
• Bilateral opacities on chest x-ray
• Arterial to inspired oxygen ratio (PₐO2/FᵢO2) of ≤300 on positive end-expiratory pressure (PEEP) or continuous positive airways pressure (CPAP) of ≥5cm H2O
• Presentation cannot be fully explained by cardiac failure or fluid overload 

ARDS can be stratified by severity according to oxygenation defined by PₐO2/FiO2 ratio:

• Mild – PₐO2/FᵢO2 200-300mmHg
• Moderate – 100-199mmHg
• Severe – <100mmHg

Investigations

Often, the diagnosis of ARDS can be made on the basis of basic clinical and chest x-ray findings, and the priority should be initiating supportive management in a timely fashion. However, there is still an important role in continuing investigations alongside supportive care, both to differentiate between ARDS and acute pulmonary oedema and to establish the underlying cause. Some of the below investigations can be useful in certain situations:

• Chest x-ray – an essential investigation, as diffuse pulmonary infiltrates on a plain radiograph, are part of the diagnostic criteria for ARDS. 
• Lung ultrasound – increasingly, point of care lung ultrasound use in critical care can be used to make the radiological diagnosis in the place of x-ray, looking for B-lines associated with an irregular pleural morphology with spared areas (5).
• Arterial blood gas monitoring – frequent ABG monitoring helps determine the PaO2 to FiO2 ratio for both diagnosis and to determine progression and oxygen requirements.
• Transthoracic echocardiogram (TTE) – the role of TTE here is to rule out the differential diagnosis of pulmonary oedema due to left ventricular dysfunction and/or valvular disease.
• Bronchoscopy – useful where the underlying aetiology is unclear, as samples can be taken and sent for culture, biochemistry and cytology testing.
• Lung biopsy – this is a very invasive test and not routinely done for all patients; however, biopsy can be a useful investigation where there is a lot of diagnostic uncertainty regarding aetiology of the ARDS. Histopathologically, the diagnosis of ARDS can be confirmed by the appearance of diffuse alveolar damage (DAD).

Image Source: Wikimedia Commons (2017). ARDSSevere, Licensed under a creative commons licence. Available for free at: https://commons.wikimedia.org/wiki/File:ARDSSevere.png (Accessed: 6 June 2022).

Differential diagnoses

Pulmonary oedema

Cardiogenic pulmonary oedema is the most important differential for ARDS, and when severe, can have an almost identical appearance on chest x-ray. Whilst both can be associated with progressive shortness of breath and worsening oxygen requirement, certain signs on examination can help differentiate the two. A raised JVP, presence of a third heart sound and peripheral oedema are all present in pulmonary oedema but not in ARDS. There also may be clues in the history, such as a recent acute coronary syndrome or known pre-existing valvular disease. It is important to distinguish the two, as pulmonary oedema can respond well to the timely initiation of IV diuretics. 

Pulmonary haemorrhage

Diffuse alveolar haemorrhage can have a similar radiological appearance to ARDS. Clinically, remain clinically suspicious of pulmonary haemorrhage with any patient presenting with haemoptysis or a very acute onset breathlessness.

Pulmonary vasculitis 

Conditions such as granulomatosis with polyangiitis (GPA) and eosinophilic granulomatosis with polyangiitis (EGPA) can present with bilateral infiltrates on chest x-ray and a similar symptom profile to ARDS. However, patients can also have evidence of multi-system involvement, such as vasculitic skin rash and renal impairment. Differentiate this patient group by sending off an autoimmune screen, including ANA, ANCA and double-stranded DNA (dsDNA).

Lymphangitic carcinomatosis 

In patients with disseminated malignancy presenting with unexplained worsening shortness of breath and dry cough suspect pulmonary lymphangitis, where the lymphatic channels in the lungs are infiltrated by malignant cells. Presentation is often too indolent here to meet the diagnostic criteria for ARDS (3).

Management

The management of ARDS is largely supportive whilst treating the underlying condition. The vast majority of patients with ARDS require mechanical ventilatory support. The main principles of supportive management are as follows:

• Lung protective ventilation – the ventilation approach evidenced to produce the best mortality outcomes involves using lower tidal volumes of 6-8mL/kg to avoid barotrauma, as tolerated to maintain O2 saturations of 88-95%, with permissive hypercapnia.
• Venous thromboembolism prophylaxis with low molecular weight heparin
• Stress ulcer prophylaxis with a proton pump inhibitor, e.g., omeprazole 
• Nutritional support with NG feeding (6)

References

• Confalonieri M, Salton F, Fabiano F. Acute respiratory distress syndrome. European Respiratory Review. 2017;26(144):160116.
• Pierrakos. Acute Respiratory Distress Syndrome: Pathophysiology and Therapeutic Options. Journal of Clinical Medicine Research. 2012;4(1).
• UpToDate [Internet]. www.uptodate.com. [cited 2022 Jun 4]. Available from: https://www.uptodate.com/contents/acute-respiratory-distress-syndrome-clinical-features-diagnosis-and-complications-in-adults
• Acute Respiratory Distress Syndrome Definitions • LITFL [Internet]. Life in the Fast Lane • LITFL • Medical Blog. 2019. Available from: https://litfl.com/acute-respiratory-distress-syndrome-definitions/
• Corradi F, Brusasco C, Pelosi P. Chest ultrasound in acute respiratory distress syndrome. Current Opinion in Critical Care. 2014 Feb;20(1):98–103.
• Saguil A, Fargo M. Acute Respiratory Distress Syndrome: Diagnosis and Management. American Family Physician [Internet]. 2012 Feb 15 [cited 2022 Jun 5];85(4):352–8. Available from: https://www.aafp.org/pubs/afp/issues/2012/0215/p352.html

Sarcoidosis

Background

Epidemiology

Sarcoidosis is a multi-system disorder which can affect most organs in the body. Pulmonary sarcoidosis is the most common presentation, affecting up to 90% of patients with the disease and accounting for a large proportion of morbidity and mortality. Prevalence of sarcoidosis in the UK is around 175 cases per 100,000 population, affecting males and females equally. Most people are diagnosed between the ages of 30 and 60. There is a higher prevalence among people of Irish and Afro-Caribbean descent, and therefore, across the UK, cases are most concentrated in London, Scotland and Northern Ireland due to the prominence of these population groups in those regions (1).

Pathophysiology

The exact aetiology of sarcoidosis is unclear, although it is characterised by the accumulation of non-caseating granulomas in various tissues, including, but not limited to, the lungs. The granulomata are comprised of accumulated macrophages, CD4-positive T-lymphocytes and multinucleated giant cells. There is an associated increased production of cytokines such as tumour necrosis factor alpha, (TNF-α), interferon-gamma (IF-γ), interleukin-2 (IL-2) and transforming growth factor beta (TGF-β), mediating a widespread inflammatory process. These granulomata have a propensity for the thoracic lymph node sites, but can also form in the lung parenchyma (2).

Presentation

Sarcoidosis can have an indolent and non-specific presentation with multi-systemic symptoms and can sometimes be a challenging diagnosis to make. Patients with lymph-node limited disease may be entirely asymptomatic, and the respiratory exam is usually normal in patients with pulmonary sarcoidosis. Below are outlined some of the most common symptoms and signs based on site of disease. 

Signs and symptoms

Symptoms and signs can be best appreciated by delineating them by different presentations of disease. Patients often have multiple groups of presenting symptoms depending on their sites of disease. 

Lymph node disease:

• Fevers
• Night sweats
• Fatigue
• Weight loss
• Myalgia

Lung parenchymal disease: 

• Dyspnoea
• Reduced exercise tolerance 
• Cough
• Pleuritic chest pain
• Chest tightness

Skin manifestations:

• Erythema nodosum – tender, erythematous nodules found mostly on the shins
• Erythema multiforme – target lesions
• Lupus pernio – violaceous, plaque-like lesions on the nose and cheeks which, when biopsied, show non-caseating granulomas
• Calcinosis cutis – skin deposition of calcium
• Skin plaques
• Papules and papulonodules
• Subcutaneous nodules
• Erythroderma 
• Nummular eczema
• Nail changes such as pitting, scarring, thickening and clubbing (3)

Image Source: Wikimedia Commons (2018). Erythema Nodosum, Licensed under a creative commons licence. Available for free at: https://commons.wikimedia.org/wiki/File:Erythema_Nodosum.jpg (Accessed: 6 June 2022).

Image Source: Wikimedia Commons (2010). Lupus Pernio 01, Licensed under a creative commons licence. Available for free at:  https://commons.wikimedia.org/wiki/File:Lupus_pernio_01.jpg (Accessed: 6  June 2022).

Eye manifestations:

• Uveitis – blurred vision, red, watery eyes, photophobia
• Scleritis/episcleritis
• Proptosis
• Iris nodules
• Lacrimal gland involvement, causing sicca syndrome

Cardiac manifestations:

• Arrhythmias, most commonly conduction abnormalities
• Sudden cardiac death from ventricular arrhythmias or complete heart block
• Symptoms of congestive cardiac failure such as shortness of breath, peripheral oedema 
• Symptoms and signs of pulmonary hypertension

Neurological manifestations – neurosarcoidosis can affect any part of the nervous symptom, most commonly:

• Cranial nerve palsies, commonly facial nerve palsy, optic nerve dysfunction
• Brain parenchyma can be affected, resulting in a range of neurological symptoms and signs, including cognitive impairment 
• Peripheral neuropathy
• Myelopathy – causing leg weakness and sensory changes 
• Meningitis 

Musculoskeletal manifestations:

• Polyarthritis, often acute 
• Dactylitis 

Endocrine and metabolic manifestations:

• Parotid gland enlargement
• Hyperprolactinaemia, resulting in amenorrhoea and galactorrhoea in women
• Hypercalcaemia, resulting in renal stones 

Gastrointestinal manifestations:

• Asymptomatic liver enzyme derangement
• Hepatomegaly
• Jaundice
• Right upper quadrant pain

Haematological manifestations – can produce non-specific symptoms related to the following blood dyscrasias:

• Lymphadenopathy 
• Non-specific symptoms of fatigue, easy bruising and infection can also occur with lymphopenia, anaemia and thrombocytopenia.

Lofgren’s syndrome – this is an acute presentation of sarcoidosis characterised by bilateral hilar lymphadenopathy, erythema nodosum and polyarthralgia, often predominantly affecting the ankles. 

Diagnosis

Investigations

• Blood tests are primarily useful for assessing for the complications of sarcoidosis and monitoring on treatment rather than being diagnostic in and of themselves. All patients should have: 
  • Full blood count
  • Bone profile (including serum calcium)
  • Liver function tests
  • Urea and electrolytes
  • Serum angiotensin converting enzyme (ACE) level 
• 12-lead ECG – important as a baseline screening test for cardiac sarcoid, which most commonly presents with arrhythmia.
• Chest x-ray – essential for the diagnosis of pulmonary sarcoidosis; disease staging is based on radiographic appearance (see table 5). In cases where the clinical and radiological picture is clear cut, the diagnosis can be made based on chest x-ray alone without need for further imaging. Most commonly, there is a symmetrical hilar lymphadenopathy, and if parenchymal involvement is present, it tends to be mid and upper zone predominant nodular or reticulonodular shadowing. Where there is progression to fibrosis, this is upper lobe predominant. Surveillance chest x-ray imaging is used on a 3-monthly basis. 
• High-resolution CT chest – can be helpful to further characterise appearances where there is diagnostic uncertainty. It is also more sensitive than chest x-ray, so can be used to detect disease where there is a clinical suspicion in the context of a normal plain radiograph.
• FDG-PET – occasionally used in scenarios of diagnostic uncertainty – looks for active inflammatory disease and is useful for detecting cardiac involvement. 
• Pulmonary function testing – can often be normal, but in the presence of fibrosis will show a restrictive lung defect picture.
• Bronchoscopy and biopsy – where there is any diagnostic uncertainty regarding alternative differentials, such as lymphoma and tuberculosis, biopsy is the only way to reach a confirmed diagnosis. On the biopsy sample, a CD4:CD8 ratio >4 in the absence of other inflammatory cells is highly specific for a diagnosis of sarcoidosis. 
  • If there are any cutaneous lesions, they can be biopsied in the first instance. 
  • Endobronchial ultrasound (EBUS) guided biopsy should be undertaken if there is primarily lymph node disease.
  • Transbronchial biopsies are used if there is primarily parenchymal disease present (4).

Table 5 – Scadding criteria for radiographic staging of pulmonary sarcoidosis

Scadding stage	Chest x-ray findings
0	Normal
I	Bilateral hilar lymphadenopathy alone
II	Bilateral hilar lymphadenopathy with pulmonary infiltrates
III	Pulmonary infiltrates without hilar lymphadenopathy
IV	Pulmonary fibrosis

Table 5 Source: Thillai M, Atkins CP, Crawshaw A, Hart SP, Ho L-P, Kouranos V, et al. BTS Clinical Statement on pulmonary sarcoidosis. Thorax. 2020 Dec 2;76(1):4–20.

Image Source: Wikimedia Commons (2016). HilarAdenopathy, Licensed under a creative commons licence. Available for free at: https://commons.wikimedia.org/wiki/File:HilarAdenopathy.png (Accessed: 6 June 2022).

Differential diagnoses

Lymphoma

For patients presenting with bilateral hilar lymphadenopathy, lymphoma is an important differential. They can also present with “B-symptoms” of weight loss, night sweats and persistent fatigue, all of which can also occur with sarcoidosis. Differentiating features would include painless lymphadenopathy elsewhere and splenomegaly. Full blood count and blood film are minimally invasive investigations which can help with the diagnosis, but if there is a significant diagnostic uncertainty, a lymph node biopsy or bone marrow aspirate should be undertaken.

Tuberculosis

Pulmonary tuberculosis (TB) presents with cough, haemoptysis and shortness of breath in addition to systemic symptoms such as weight loss, fevers and night sweats. Appearance of hilar lymphadenopathy can be similar to sarcoidosis on chest x-ray. TB is characterised by caseating granulomas, whereas sarcoidosis is associated with non-caseating granulomas. Travel and exposure history are important in delineating risk of an infective cause of symptoms, particularly where there are red flag symptoms such as haemoptysis. It is important to rule out TB prior to giving immunosuppressive therapy.

Interstitial lung disease 

In patients with fibrosis on imaging, it is important to consider other forms of interstitial lung disease. Diseases of occupational exposure, such as berylliosis and silicosis, can have a similar CT appearance, so a thorough occupational history is key.

Management

The decision to commence pharmacological treatment in sarcoidosis should be considered based on the expected morbidity and mortality for the individual patient, as well as potential impacts on their quality of life. Some patients have minimal symptoms from their sarcoidosis, and introducing immunosuppressant therapy with associated side effects is not without risk. Attention should also be paid to managing patient symptoms such as fatigue with supportive lifestyle measures, such as structured exercise routines and counselling on sleep hygiene.

Steroids

In pulmonary sarcoidosis, when steroids are indicated, a commonly used regime would be 20-40mg prednisolone once daily for 4-6 weeks, followed by a tapering period to a maintenance dose of 5-10mg per day. In life-threatening disease or extrapulmonary cases such as neurosarcoidosis or cardiac sarcoid, high-dose intravenous methylprednisolone can be used as initiation therapy. 

Second line immunosuppression

Indications for second-line immunosuppressive therapy:

• Progression of pulmonary disease on steroid treatment
• Unacceptable symptom burden 
• Unacceptable steroid side effects or strong patient aversion to steroid treatment 
• Inability to taper steroids dose to below 10-15mg prednisolone per day without rebound symptoms
• Significant contraindications to long-term steroid therapy, such as obesity, diabetes mellitus or osteoporosis

There are multiple agents of choice for steroid-sparing agents.

• Methotrexate – an anti-folate medication, introduced as a once weekly regimen of 5-10mg, it can be uptitrated to 20mg as tolerated. Once weekly folic acid 5mg should be given concurrently to reduce risk of myelosuppression. Potential side effects include pneumonitis, hepatic fibrosis and teratogenicity (both male and female patients should be counselled on this risk). 
• Azathioprine – an inhibitor of purine synthesis, it causes immunosuppression by interrupting DNA and RNA formation. This affects lymphocyte proliferation in sarcoidosis. Started at 50mg once daily, it can be uptitrated to a therapeutic dose of 2mg/kg/day. Side effects include pancytopenia, increased risk of malignancy, nausea, vomiting, diarrhoea, rash, malaise and fever. Patients should have thiopurine methyltransferase (TPMT) levels tested prior to commencing treatment; those with a pre-existing enzyme deficiency are more at risk of pancytopenia, and an alternative agent should be used. 
• Mycophenolate mofetil – an inhibitor of lymphocyte proliferation, this can be started at a dose of 1-1.5g twice a day. Side effects include gastrointestinal disturbances, teratogenicity as well as a small risk of neutropenia.
• Leflunomide – works as an anti-metabolite, similar to methotrexate. Can be used in preference to methotrexate due to a lower gastrointestinal toxicity profile, although it can still cause this. Other side effects include hepatotoxicity, hypertension and peripheral neuropathy.
• Cyclophosphamide – this is an alkylating agent that results in increased cell apoptosis, reducing circulating lymphocyte numbers. Use in sarcoidosis is rare due to the high side effect profile, which includes pancytopenia, haemorrhagic cystitis, nausea, vomiting, diarrhoea and alopecia. 
• Hydroxychloroquine – works by increasing lysosomal pH in antigen-presenting cells. It is rarely used as monotherapy in pulmonary fibrosis, but is commonly used in cutaneous and joint disease and to treat fatigue. It can also be used as an adjunctive therapy to help with steroid weaning, at a dose of 200mg twice a day. Side effects include cardiac and retinal toxicity, in addition to gastrointestinal symptoms and headache. Prior to commencing treatment, all patients must have a baseline ECG to ensure there is no pre-existing long QTc interval, as well as a baseline ophthalmic examination. 

All second-line immunosuppressive agents require frequent blood test monitoring of FBC, U&Es and LFTs. The following regime is recommended:

• 2-weekly for the first 2-months
• If stable, can reduce frequency to monthly for the next 6-months
• If stable, can reduce frequency to 3-monthly, which should be ongoing whilst the patient is on treatment

Biological agents and antifibrotics

• Infliximab is an anti-tumour necrosis factor (anti-TNF) agent. TNF is one of the cytokines that has a significant pro-inflammatory effect in sarcoidosis, promoting granuloma formation; inhibiting it, therefore, has an important therapeutic effect. Infliximab can be used as a third-line agent in combination therapy with methotrexate or azathioprine, given initially as 2-weekly infusions and then 6-8 weekly for maintenance. Side effect profile includes immunosuppression, with increased susceptibility to mycobacterium and invasive fungal infections, infusion reactions, alopecia, visual field defects and increased risk of pulmonary embolism. Prior to starting treatment, patients should be screened for latent TB infection using Interferon Gamma Release Assay (IGRA) testing. If latest TB is detected, patients should complete anti-TB treatment prior to starting infliximab. 
• Antifibrotic medications such as pirfenidone and nintedanib are only licensed in the UK for idiopathic pulmonary fibrosis, but recent studies have shown a positive therapeutic effect in fibrosis secondary to sarcoidosis (4).

Lung transplantation

Bilateral lung transplantation is an option for patients with advanced fibrosis or pulmonary hypertension who have a significant, acute drop in pulmonary function (e.g., a 10% drop in FVC over a 6-month period) (4). 

References

• Sarcoidosis statistics | British Lung Foundation [Internet]. statistics.blf.org.uk. Available from: https://statistics.blf.org.uk/sarcoidosis
• UpToDate [Internet]. www.uptodate.com. Available from: https://www.uptodate.com/contents/pathology-and-pathogenesis-of-sarcoidosis
• Sarcoidosis: Symptoms, Causes, and Images – DermNet [Internet]. dermnetnz.org. Available from: https://dermnetnz.org/topics/sarcoidosis
• Thillai M, Atkins CP, Crawshaw A, Hart SP, Ho L-P, Kouranos V, et al. BTS Clinical Statement on pulmonary sarcoidosis. Thorax. 2020 Dec 2;76(1):4–20.