Respiratory - Pulmonary vascular disease & eosinophilia Flashcards by intesar Nur (2024)

These are summarized in Virchow’s triad:

1) Venous stasis (e.g. CCF)
2) Increased blood coagulability
3) Damage to vessel endothelium (e.g. peripheral vascular disease)

Conditions producing these include immobility, surgical or accidental trauma, heart disease, pregnancy, oral contraceptives, obesity and intravascular catheters.

These thrombi are formed in areas of less active blood flow most often in veins of the lower extremities (and in the periprostatic or other pelvic veins).

They are dark red with a higher concentration of RBCs than arterial thrombi. Lines of Zahn are not prominent or may be absent altogether.

They are often associated with concurrent venous inflammatory changes. Inflammation of veins from thrombus formation is referred to as thrombophlebitis.

Large emboli impact in major pulmonary arteries or sit at the bifurcation of both the right and left main trunks - “saddle embolus”.

Small emboli lodge in more peripheral segmental arteries.

Infarction is necrosis resulting from ischaemia caused by obstruction of blood flow. The necrotic tissue is referred to as an infarct.

Infarcts can either be anaemic of hemorrhagic.
Hemorrhagic infarcts are red infarcts, in which red cells ooze into the necrotic area. They occur characteristically in the lung and gastrointestinal tract as the result of arterial occlusion. These sites are loose, well vascularised tissues with redundant arterial blood supplies (in the lung from the pulmonary and bronchial systems; in the GIT from multiple anastomoses between branches of mesenteric artery) and a haemorrhage into the infarct occurs from the non-obstructed portion of the vasculature.

Thrombotic disorders are classified as either anti-thrombotic (haemorrhagic) leading to pathologic bleeding states such as haemophilia and vWD. They can also be prothrombotic leading to hypercoagulability with pathologic thrombus.

These can be summarised as:

1) Hereditary thrombophilias (factor V liden, protein C and S deficiency, prothrombin 20210A transition etc)
2) Antiphospholipid syndrome
3) DIC
4) Heparin induced thrombocytopaenia (HIT) syndrome

The heart can undergo structural changes following a PE which leads to impaired function. Acute right ventricular dilatation can occur with massive obstruction of the pulmonary artery. This leads to acute RVF. Systemic shock is due to decreased pulmonary blood flow leading to decreased left ventricular filling and output. There is an additional effect of hypoxia on heart muscle function.

Right ventricular hypertrophy tends to occur in cases of recurrent pulmonary thromboembolism causing pulmonary hypertension.

These are highly dependent on the size of the embolus and the status of the cardiopulmonary system:

1) Silent: up to 80% of emboli are clinically silent because they are small and are often lysed by fibrinolysins. Infarction does NOT occur in these circ*mstances, and in the absence of significant myocardial disease (e.g. HF) because of adequate collateral bronchial circulation
2) Infarction
3) Recurrent emboli
4) Sudden death: massive embolism with obstruction of a large artery can result in death or acute right sided heart failure followed by death
5) Circulatory shock: with massive emboli
6) Chronic pulmonary hypertension: an uncommon but important cause which may be difficult to diagnose
7) Abscess: some infarcts become secondarily infected and form abscesses. Alternatively an embolus may be septic

These vary with the size and multiplicity of the infarcts:

1) Pulmonary dysfunction: due to loss of lung tissue
2) Pulmonary vascular obstruction
3) Pleurisy and pleural effusion: often haemorrhagic
4) Healing: resulting in a fibrous scar
5) Septic infarction: primary septic embolism or secondary infection leading to abscess formation

The clinical features of pulmonary embolism depend on the size and severity of embolism. Broadly speaking important features in at risk patients to watch out for include: dyspnoea, pleuritic chest pain, haemoptysis, syncope, fever.

Signs: pyrexia, cyanosis, tachypnoea, tachycardia, hypotension, raised JVP, pleural rub, pleural effusion, calf swelling (look for cause).

If an acute minor PE is associated with infarction it tends to produce pleuritic chest pain, haemoptysis and fever.

Consider the diagnosis of PE in all patients with unexplained breathlessness, pleuritic pain, haemoptysis or sudden collapse.

Chest x ray, ECG and arterial blood gases are essential first line investigations:

• CXr: may be normal; can show dilated pulmonary artery small effusion, wedge shaped opacities or cavitation (rare)
• ECG: may be normal or show tacchycardia, RBBB, RV strain (inverted T in V1 to V4) or classic S1Q3T3 pattern
• ABG: hypoxia and hypocapnia (due to hyperventilation)

FBC, U&E and baseline clotting important

D-dimer is useful in excluding a PE but not in confirming it - i.e. only perform in those patients WITHOUT a high probability of a PE. A negative D-dimer test effectively excludes a PE in those with low or intermediate clinical probability and imaging is NOT required. However a positive test does not prove a diagnosis of a PE and imaging is required.

(Wells score suggests that score of >3 carries a high probability of a PE)

CTPA is the recommended first line imaging modality which can show a clot down to the 5th order pulmonary arteries.

V/Q scanning is now rarely performed except on young patients (e.g. females) because the dose of radiation may be too high.

1) Anticoagulate with LMWH
2) Start warfarin
3) Stop heparin* when INR is >2 and continue warfarin for a minimum of 3 months, aim for an INR of 2-3

Warfarin has a prothrombotic effect for the first 72 hours so heparin cover is required.

For a massive PE:

1) Thrombolysis with alteplase 10mg IV over 1 min then 90mg IV over 2h
2) Consider placement of a vena caval filter in patients who develop emboli despite adequate anticoagulation

Heparin can be used as an unfractionated molecule or as low molecular mass molecules.

Unfractionated heparin has a very short half life, which depends on the dosage and route of administration. LMWHs have a much longer duration of action and half life because they do not bind to plasma proteins or to endothelial cells (like unfractionated forms do). LMHW is the drug of choice in pregnant women requiring anticoagulation.

Examples of low molecular weight heparin include ENOXPARIN (clexane) and TINZAPARIN

For unfractionated heparin, the degree of anticoagulation is monitored by measuring the activated partial thromboplastin time (APPT) with the aim of therapy to keep the APPT between 1.5 and 2 times as normal.

As LMWH have much more predictable effects, provided that the correct dosage is given, routine monitoring is not required.

• bleeding disorders
• recent severe bleeding
• severe hypertension
• severe liver disease

• haemorrhage
• osteoporosis - usually only after prolonged use
• heparin induced thrombocytopaenia
• hyperkalaemia
• urticaria and angiodema

ENOXAPARIN 1.5mg/kg s.c.o.d for 5 days minimum and until adequate oral anticoagulation is established.

Start warfarin therapy day on day 1 using dosage titration to achieve a stable INR of 2.0-3.0

For first DVT continue oral anticoagulation for 3 months.
For second DVT continue anticoagulation for 6 months.
For third or subsequent DVT, investigate for an underlying cause and give warfarin for life.

ENOXAPARIN 1.5mg/kg s.c.o.d until adequate oral anticoagulation achieved.

Start warfarin therapy on day 1 using dosage titration to achieve stable INR of 2.0-3.0

For first episode of PE continue treatment for minimum of 3 months .
For second episode or subsequent PE, investigate for an underlying cause and give warfarin for life.

The capillary wall is normally fairly permeable to water and small molecules, but not to proteins. Alveolar cells are much less permeable to all substances. Normally, due to the balance between the hydrostatic pressure forcing fluid out of the capillaries and colloid osmotic pressure preventing such loss, only a small amount of fluid passes into the interstitium.

This drains to the peribronchial/ perivascular space where it enters the lymphatic channels. If excess fluid passes out of the capillaries and the flow rate exceeds the lymphatic drainage capacity, accumulation within the peribronchial space and then the interstitium occurs. Fluid eventually passes into the alveolar spaces.

There are a number of causes of pulmonary oedema, most of which relate to alterations in Starlings forces regulating fluid movement across capillary membranes.:

1) Increased capillary hydrostatic pressure
2) Increased capillary permeability - e.g. ARDS
3) Decreased plasma oncotic pressure
4) Lymphatic obstruction
5) Decreased interstitial pressure - large mechanical forces acting on the interstitium, e.g. rapid expansion of the lung after evacuation of a large pleural effusion
6) Unknown or uncertain mechanisms - e.g. neurogenic pulmonary oedema following traumatic brain injury

This is the commonest cause of pulmonary oedema and occurs in a number of circ*mstances. Increased capillary hydrostatic pressure limits reabsorption at the venous end of capillaries leading to increased fluid extravasation.

1) Left sided heart failure: in MI, aortic valve disease, mitral regurgitation and tachyarrhythmias
2) Pulmonary venous hypertension: e.g. in mitral stenosis
3) Constrictive pericarditis or pericardial effusion
4) Fluid overload: e.g. excess infusion of crystalloid solutes

Hypoproteinaemia due to:

• malnutrition
• Nephrotic syndrome
• IV infusion of hypotonic solutes
• Liver failure

The lungs are heavy and congested. Fluid flows from the cut surfaces and is often sen in the large airways of fatal cases.

Microscopically there is filling of alveoli with proteinaceous fluid, widening of the interstitium and congestion of the capillaries.

The X ray findings depend on whether the cause is cardiogenic or non cardiogenic.

In cardiogenic cases there can be:

• bilateral alveolar shadowing: oedema in the alveoli; if acute cardiogenic cause shadowing spreads out from the hilar in a “bats wing” appearance
• upper lobe diversion: lower zone hypoxia causes hypoxic pulmonary vasoconstriction diverting blood to the upper lobes
• Kerley B lines: horizontal lines that reach the pleural surface; caused by fluid between the interlobular septa
• cardiomegaly
• cardiac pathology signs: e.g. stenostomy wires, prosthetic valve, pacemaker

In non cardiogenic cases there can be:

• diffuse alveolar shadowing: present in both upper and lower lobes
• normal heart size (but this can also occur in cardiogenic cases as well!)

This is caused by chronic left sided heart disease - e.g. myocardial failure due to ischaemia, mitral stenosis or hypertensive heart disease.

The lung is firm, fibrous and brown, with congestion of alveolar vessels, fibrous thickening of the alveolar walls and pigmented macrophages - “heart failure cells” in the alveoli. There can also be atheroma in larger vessels.

The main effect is pulmonary hypertension.

A pulmonary arterial pressure of > 25mmHg at rest.

Normally, pulmonary pressures are much lower than the systemic system.

Normal pulmonary blood flow is 5-8L/min at rest. Normal pressures are 16-17mmHg, and with exercise the flow rate increases up to 16L/min but the pressure does not change significantly.

The pulmonary circulation transmits the total right ventricular output with minimum resistance through the lungs. The vessels are therefore compliant and thin walled. Elastic arteries extend as far as the end of the cartilagenous bronchi and the muscular arteries are short, ending at the level of the respiratory bronchioles.

The arterioles soon lose their muscle and consist mostly of intima, external elastic tissue and adventitia.

1) Precapillary: caused by increased flow or by increased resistance. Alveolar walls are normal
2) Capillary: due to destruction of alveoli or distortion of the alveolar capillary bed
3) Postcapillary: from passive congestion of alveolar parenchyma

There are several types of pulmonary hypertension that are currently grouped using the Dana Point (2008) classification.

Group 1 PH, also termed pulmonary arterial hypertension (PAH) comprised heritable (hPAH) and idiopathic PAH (iPAH) and also PH associated with a number of other conditions (aPAH) such as connective tissue disease.

Both hPAH and iPAH are characterised by a decreased expression of bone morphogenic protein receptor type 2 (BMPR2) which, usually in hPAH and sometimes in iPAH is associated with mutations in the BMPR2 gene.

Groups 2-5 are forms of secondary PH:
- Group 2 are caused by left heart disease, chiefly ventricular failure or mitral and/or aortic valve disease which results in increased left atrial pressure that backs up across the pulmonary artery (post capillary)

• Group 3 PH is associated with lung diseases such as COPD, obstructive sleep apnoea and cystic fibrosis. The common factor being the presence of alveolar hypoxia
• Group 4 PH is associated with chronic thromboembolic disease with a persistent blockage of pulmonary arteries arising from venous thromboembolism
• Group 5 represents PH associated with a heterogeneous set of conditions such as CML, sarcoidosis and thyroid disease

This is a group of rare diseases, mainly of unknown aetiology, which cause chest X ray abnormalities associated with raised eosinophil count in peripheral blood.

Diseases included in this category include:

(i) acute eosinophilic pnuemonia
(ii) chronic eosinophilic pneumonia
(iii) hypereosinophilic syndrome
(iv) Churg-Strauss syndrome

Other diseases that cause pulmonary disease in association with eosinophilia are: asthma, fungal diseases (including allergic bronchopulmonary aspergillosis, parasitic infection (e.g. filariasis), drug reactions, polyarteritis nodosa and Hodgkins disease.

Acute and chronic eosinophilic pneumonia are more common in women, peak incidence is 40-50 years. Fifty percent of patients have asthma. Eosinophilic pneumonia responds well to treatment and recurrence is uncommon.

Chronic disease responds less well to treatment and recurrence may require long term steroid treatment.

They are both characterised by fever, dry cough, dyspnoea, chest pain and weight loss.

This is very rare , is usually of unknown cause (although it occurs more often in the tropics where it may relate to parasitic infection). It often responds poorly to treatment. Complicating cardiac failure can occur and carries a poor prognosis.

Clinical features include cough, malaise, and cardiac failure (due to myocardial infiltration).

Nasal/ sinus disease leads to congestion and nose bleeds. Nasal septum perforation leading to saddle nose occurs in up to 30% of cases.

Subglottic stenosis occurs in 20% and causes breathlessness (which may be severe), voice change and cough. The diagnosis of subglottic stenosis is suggested by flow-volume loops; this responds very poorly to systemic therapy but may respond to mechanical dilation and local injection of corticosteroids.

• Parenchymal disease: two thirds of those with parenchymal involvement have symptoms, one third only have asymptomatic CXR abnormalities
• Variable changes: bilateral nodular infiltrates, cavitatary disease and pulmonary haemorrhage
• 15% have stenosis of endobronchial airways leading to cough, wheezing, breathlessness and haemoptysis

The diagnosis is made from a biopsy showing a necrotizing vasculitis with granuloma formation in a clinically relevant setting. Antibodies against neutrophil cytoplasm are found, in two staining patterns:

• Cytoplasmic ANCA (cANCA): the antigen is proteinase-3. cANCA is found in 70-90% of WG. Though cANCA has a high specificity and sensitivity for WG, it should not be relied on in isolation.
• Perinuclear ANCA (pANCA): the antigen is usually myeloperoxidase. Found in 5-10% of WG but also in many other conditions.

Untreated WG has a VERY HIGH mortality. Treatment with cyclophosphamide and prednisolone dramatically reduces morbidity and mortality: 75% achieve complete disease remission.

Drug related side effects (sepsis from immunosuppression, late malignancy) are common. Pneumocystis infection is so common that septrin prophylaxis is justified.